研究者詳細 - 中司　敦子

論文 - 中司　敦子

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GRP78 Contributes to the Beneficial Effects of SGLT2 Inhibitor on Proximal Tubular Cells in DKD 査読

Atsuko Nakatsuka, Satoshi Yamaguchi, Jun Wada

Diabetes 73 ( 5 ) 763 - 779 2024年2月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：American Diabetes Association

The beneficial effects of sodium–glucose cotransporter 2 (SGLT2) inhibitors on kidney function are well-known; however, their molecular mechanisms are not fully understood. We focused on 78-kDa glucose-regulated protein (GRP78) and its interaction with SGLT2 and integrin-β1 beyond the chaperone property of GRP78. In streptozotocin (STZ)-induced diabetic mouse kidneys, GRP78, SGLT2, and integrin-β1 increased in the plasma membrane fraction, while they were suppressed by canagliflozin. The altered subcellular localization of GRP78/integrin-β1 in STZ mice promoted epithelial mesenchymal transition (EMT) and fibrosis, which were mitigated by canagliflozin. High-glucose conditions reduced intracellular GRP78, increased its secretion, and caused EMT-like changes in cultured HK2 cells, which were again inhibited by canagliflozin. Urinary GRP78 increased in STZ mice, and in vitro experiments with recombinant GRP78 suggested that inflammation spread to surrounding tubular cells and that canagliflozin reversed this effect. Under normal glucose culture, canagliflozin maintained sarco/endoplasmic reticulum (ER) Ca2+-ATPase (SERCA) activity, promoted ER robustness, reduced ER stress response impairment, and protected proximal tubular cells. In conclusion, canagliflozin restored subcellular localization of GRP78, SGLT2, and integrin-β1 and inhibited EMT and fibrosis in DKD. In nondiabetic chronic kidney disease, canagliflozin promoted ER robustness by maintaining SERCA activity and preventing ER stress response failure, and it contributed to tubular protection.

Article Highlights

DOI： 10.2337/db23-0581

A Vaspin–HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease 査読国際誌

Atsuko Nakatsuka, Satoshi Yamaguchi, Jun Eguchi, Shigeru Kakuta, Yoichiro Iwakura, Hitoshi Sugiyama, Jun Wada

Communications Biology 4 ( 1 ) 373 - 373 2021年12月

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

<title>Abstract</title>Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD). However, the roles of visceral adipose tissue-derived serine protease inhibitor (vaspin) in the development of DKD is not known. We found vaspin maintains PTCs through ameliorating ER stress, autophagy impairment, and lysosome dysfunction in DKD. <italic>Vaspin</italic>−/− obese mice showed enlarged and leaky lysosomes in PTCs associated with increased apoptosis, and these abnormalities were also observed in the patients with DKD. During internalization into PTCs, vaspin formed a complex with heat shock protein family A (Hsp70) member 1 like (HSPA1L) as well as 78 kDa glucose-regulated protein (GRP78). Both vaspin-partners bind to clathrin heavy chain and involve in the endocytosis. Notably, albumin-overload enhanced extracellular release of HSPA1L and overexpression of HSPA1L dissolved organelle stresses, especially autophagy impairment. Thus, vapsin/HSPA1L-mediated pathways play critical roles in maintaining organellar function of PTCs in DKD.

DOI： 10.1038/s42003-021-01902-y

その他リンク： http://www.nature.com/articles/s42003-021-01902-y

Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3). 査読国際誌

Asami Ueno, Yasuhiro Onishi, Koki Mise, Satoshi Yamaguchi, Ayaka Kanno, Ichiro Nojima, Chigusa Higuchi, Haruhito A Uchida, Kenichi Shikata, Satoshi Miyamoto, Atsuko Nakatsuka, Jun Eguchi, Kazuyuki Hida, Akihiro Katayama, Mayu Watanabe, Tatsuaki Nakato, Atsuhito Tone, Sanae Teshigawara, Takashi Matsuoka, Shinji Kamei, Kazutoshi Murakami, Ikki Shimizu, Katsuhito Miyashita, Shinichiro Ando, Tomokazu Nunoue, Jun Wada

BMJ open diabetes research & care 12 ( 3 ) 2024年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not. RESEARCH DESIGN AND METHODS: Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year. RESULTS: The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR. CONCLUSIONS: Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD. TRIAL REGISTRATION NUMBER: UMIN000011525.

DOI： 10.1136/bmjdrc-2024-004237

Inhibition of Amino Acids Influx into Proximal Tubular Cells Improves Lysosome Function in Diabetes. 査読国際誌

Yuzuki Kano, Satoshi Yamaguchi, Koki Mise, Chieko Kawakita, Yasuhiro Onishi, Naoko Kurooka, Ryosuke Sugawara, Haya Hamed Hassan Albuayjan, Atsuko Nakatsuka, Jun Eguchi, Jun Wada

Kidney360 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Inhibition of glucose influx into proximal tubular cells (PTCs) by sodium-glucose co-transporter 2 (SGLT2) inhibitors revealed prominent therapeutic impacts on diabetic kidney disease (DKD). Collectrin (CLTRN) serves as a chaperone for the trafficking of neutral amino acid transporters in the apical membranes of proximal tubular cells. We investigated the beneficial effects of reduced influx of amino acids into proximal tubular cells in diabetes and obesity model of Cltrn-/y mice. METHODS: Cltrn+/y and Cltrn-/y mice at 5 weeks of age were assigned to standard diet- (STD) and streptozotocin and high fat diet-treated (STZ-HFD) groups. RESULTS: At 22-23 weeks of age, body weight and HbA1c levels significantly increased in STZ-HFD-Cltrn+/y compared to STD-Cltrn+/y; however, they were not altered in STZ-HFD-Cltrn-/y compared to STZ-HFD-Cltrn+/y. At 20 weeks of age, urinary albumin creatinine ratio (UACR) was significantly reduced in STZ-HFD-Cltrn-/y compared to STZ-HFD-Cltrn+/y. Under the treatments with STZ and HFD, the Cltrn gene deficiency caused significant increase in urinary concentration of amino acids such as Gln, His, Gly, Thr, Tyr, Val, Trp, Phe, Ile, Leu and Pro. In proximal tubular cells in STZ-HFD-Cltrn+/y, the enlarged lysosomes with diameter of 10 μm or more were associated with reduced autolysosomes, and the formation of giant lysosomes was prominently suppressed in STZ-HFD-Cltrn-/y. Phospho-mTOR and inactive form of phospho-TFEB were reduced in STZ-HFD-Cltrn-/y compared to STZ-HFD-Cltrn+/y. CONCLUSIONS: The reduction of amino acids influx into proximal tubular cells inactivated mTOR, activated TFEB, improved lysosome function, and ameliorated vacuolar formation of PTCs in STZ-HFD-Cltrn-/y mice.

DOI： 10.34067/KID.0000000000000333

Circulating GPIHBP1 levels and microvascular complications in patients with type 2 diabetes: A cross-sectional study. 査読国際誌

Naoko Kurooka, Jun Eguchi, Kazutoshi Murakami, Shinji Kamei, Toru Kikutsuji, Sakiko Sasaki, Akiho Seki, Satoshi Yamaguchi, Ichiro Nojima, Mayu Watanabe, Chigusa Higuchi, Akihiro Katayama, Haruhito A Uchida, Atsuko Nakatsuka, Kenichi Shikata, Jun Wada

Journal of clinical lipidology 16 ( 2 ) 237 - 245 2022年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) plays a crucial role in lipolytic processing. Previous studies have shown that GPIHBP1 mutations cause severe hypertriglyceridemia and that serum GPIHBP1 levels are marginally higher in patients with coronary heart disease; however, the role of GPIHBP1 in type 2 diabetes mellitus (T2DM) remains unknown. OBJECTIVE: We investigated the association between circulating GPIHBP1 levels and the prevalence of microvascular complications in T2DM. METHODS: A total of 237 subjects with T2DM and 235 non-diabetic control subjects were enrolled in this study. Their serum GPIHBP1 levels were evaluated using ELISA assays. RESULTS: Circulating GPIHBP1 levels were higher in patients with T2DM (952.7 pg/mL [761.3-1234.6], p < 0.0001) than in non-diabetic subjects (700.6 [570.8-829.6]), but did not differ in T2DM patients with or without hypertriglyceridemia. Serum GPIHBP1 levels were significantly higher in patients with T2DM with diabetic retinopathy (DR), diabetic nephropathy (DN), and microvascular complications than in those without these complications. Multivariable logistic regression and receiver operating characteristic (ROC) curve analyses revealed that the presence of microvascular complications, but not macrovascular complications, was independently associated with serum GPIHBP1 levels, which could predict the presence of diabetic microvascular complications. CONCLUSIONS: Elevated GPIHBP1 levels are associated with microvascular complications in T2DM and may help to predict their progression.

DOI： 10.1016/j.jacl.2022.01.006

Author Correction: Lgals9 deficiency ameliorates obesity by modulating redox state of PRDX2 (Scientific Reports, (2021), 11, 1, (5991), 10.1038/s41598-021-85080-1) 査読

Tomokazu Nunoue, Satoshi Yamaguchi, Sanae Teshigawara, Akihiro Katayama, Atsuko Nakatsuka, Jun Eguchi, Toshiro Niki, Jun Wada

Scientific Reports 11 ( 1 ) 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Nature Research

The original version of this Article contained errors. In Figure 5, the size marker gel image was mistakenly placed in Panel (e). The original Figure 5 and accompanying legend appear below. Additionally in Supplementary Figure 4 and 5, the panel labels and corresponding red boxes for uncropped images were omitted. The original Supplementary Information 1 file is provided below. The original Article and accompanying Supplementary Information 1 file have been corrected. (Figure presented.).

DOI： 10.1038/s41598-021-98293-1

Lgals9 deficiency ameliorates obesity by modulating redox state of PRDX2 査読国際誌

Tomokazu Nunoue, Satoshi Yamaguchi, Sanae Teshigawara, Akihiro Katayama, Atsuko Nakatsuka, Jun Eguchi, Toshiro Niki, Jun Wada

Scientific Reports 11 ( 1 ) 5991 - 5991 2021年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

<title>Abstract</title>The adipose tissue is regarded as an endocrine organ and secretes bioactive adipokines modulating chronic inflammation and oxidative stress in obesity. Gal-9 is secreted out upon cell injuries, interacts with T-cell immunoglobulin-3 (Tim-3) and induces apoptosis in activated Th1 cells. Gal-9 also binds to protein disulfide isomerase (PDI), maintains PDI on surface of T cells, and increases free thiols in the disulfide/thiol cycles. To explore the molecular mechanism of obesity, we investigated Gal-9^−/− and Gal-9^wt/wt C57BL/6J mice fed with high fat-high sucrose (HFHS) chow. Gal-9^−/− mice were resistant to diet-induced obesity associated with reduction of epididymal and mesenteric fat tissues and improved glucose tolerance compared with Gal-9^wt/wt mice. However, the number of M1, M2 macrophages, and M1/M2 ratio in epididymal fat were unaltered. Under HFHS chow, Gal-9^−/− mice receiving Gal-9^−/− or Gal-9^wt/wt bone marrow-derived cells (BMCs) demonstrated significantly lower body weight compared with Gal-9^wt/wt mice receiving Gal-9^−/− BMCs. We identified the binding between Gal-9 and peroxiredoxin-2 (PRDX2) in sugar chain-independent manner by nanoLC-MS/MS, immunoprecipitation, and pull-down assay. In 3T3L1 adipocytes, Gal-9 knockdown shifts PRDX2 monomer (reduced form) dominant from PRDX2 dimer (oxidized form) under oxidative stress with H₂O₂. The inhibition of Gal-9 in adipocytes may be a new therapeutic approach targeting the oxidative stress and subsequent glucose intolerance in obesity.

DOI： 10.1038/s41598-021-85080-1

その他リンク： http://www.nature.com/articles/s41598-021-85080-1

Upregulation of Mir342 in Diet-Induced Obesity Mouse and the Hypothalamic Appetite Control 査読

Dongxiao Zhang, Satoshi Yamaguchi, Xinhao Zhang, Boxuan Yang, Naoko Kurooka, Ryosuke Sugawara, Haya Hamed H. Albuayjan, Atsuko Nakatsuka, Jun Eguchi, Takeshi Y. Hiyama, Atsunori Kamiya, Jun Wada

Frontiers in Endocrinology 12 2021年8月

掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers Media SA

In obesity and type 2 diabetes, numerous genes are differentially expressed, and microRNAs are involved in transcriptional regulation of target mRNAs, but miRNAs critically involved in the appetite control are not known. Here, we identified upregulation of miR-342-3p and its host gene <italic>Evl</italic> in brain and adipose tissues in C57BL/6 mice fed with high fat-high sucrose (HFHS) chow by RNA sequencing. <italic>Mir342</italic> (-/-) mice fed with HFHS chow were protected from obesity and diabetes. The hypothalamic arcuate nucleus neurons co-express <italic>Mir342</italic> and EVL. The percentage of activated NPY⁺pSTAT3⁺ neurons were reduced, while POMC⁺pSTAT3⁺ neurons increased in <italic>Mir342</italic> (-/-) mice, and they demonstrated the reduction of food intake and amelioration of metabolic phenotypes. <italic>Snap25</italic> was identified as a major target gene of miR-342-3p and the reduced expression of <italic>Snap25</italic> may link to functional impairment hypothalamic neurons and excess of food intake. The inhibition of miR-342-3p may be a potential candidate for miRNA-based therapy.

DOI： 10.3389/fendo.2021.727915

Current Status of Familial LCAT Deficiency in Japan 査読

Masayuki Kuroda, Hideaki Bujo, Koutaro Yokote, Takeyoshi Murano, Takashi Yamaguchi, Masatsune Ogura, Katsunori Ikewaki, Masahiro Koseki, Yasuo Takeuchi, Atsuko Nakatsuka, Mika Hori, Kota Matsuki, Takashi Miida, Shinji Yokoyama, Jun Wada, Mariko Harada-Shiba

Journal of Atherosclerosis and Thrombosis 28 ( 7 ) 679 - 691 2021年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japan Atherosclerosis Society

Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of the acyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM 136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) and corneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia, proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal opacity. A clinical research project aiming at gene/cell therapy is currently underway.

DOI： 10.5551/jat.rv17051

Novel Urinary Glycan Biomarkers Predict Cardiovascular Events in Patients With Type 2 Diabetes: A Multicenter Prospective Study With 5-Year Follow Up (U-CARE Study 2) 査読国際誌

Koki Mise, Mariko Imamura, Satoshi Yamaguchi, Mayu Watanabe, Chigusa Higuchi, Akihiro Katayama, Satoshi Miyamoto, Haruhito A. Uchida, Atsuko Nakatsuka, Jun Eguchi, Kazuyuki Hida, Tatsuaki Nakato, Atsuhito Tone, Sanae Teshigawara, Takashi Matsuoka, Shinji Kamei, Kazutoshi Murakami, Ikki Shimizu, Katsuhiro Miyashita, Shinichiro Ando, Tomokazu Nunoue, Michihiro Yoshida, Masao Yamada, Kenichi Shikata, Jun Wada

Frontiers in Cardiovascular Medicine 8 668059 - 668059 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers Media SA

<bold>Background:</bold> Although various biomarkers predict cardiovascular event (CVE) in patients with diabetes, the relationship of urinary glycan profile with CVE in patients with diabetes remains unclear.

<bold>Methods:</bold> Among 680 patients with type 2 diabetes, we examined the baseline urinary glycan signals binding to 45 lectins with different specificities. Primary outcome was defined as CVE including cardiovascular disease, stroke, and peripheral arterial disease.

<bold>Results:</bold> During approximately a 5-year follow-up period, 62 patients reached the endpoint. Cox proportional hazards analysis revealed that urinary glycan signals binding to two lectins were significantly associated with the outcome after adjustment for known indicators of CVE and for false discovery rate, as well as increased model fitness. Hazard ratios for these lectins (+1 SD for the glycan index) were UDA (recognizing glycan: mixture of Man5 to Man9): 1.78 (95% CI: 1.24–2.55, <italic>P</italic> = 0.002) and Calsepa [High-Man (Man2–6)]: 1.56 (1.19–2.04, <italic>P</italic> = 0.001). Common glycan binding to these lectins was high-mannose type of <italic>N</italic>-glycans. Moreover, adding glycan index for UDA to a model including known confounders improved the outcome prediction [Difference of Harrel's C-index: 0.028 (95% CI: 0.001–0.055, <italic>P</italic> = 0.044), net reclassification improvement at 5-year risk increased by 0.368 (0.045–0.692, <italic>P</italic> = 0.026), and the Akaike information criterion and Bayesian information criterion decreased from 725.7 to 716.5, and 761.8 to 757.2, respectively].

<bold>Conclusion:</bold> The urinary excretion of high-mannose glycan may be a valuable biomarker for improving prediction of CVE in patients with type 2 diabetes, and provides the rationale to explore the mechanism underlying abnormal <italic>N</italic>-glycosylation occurring in patients with diabetes at higher risk of CVE.

<bold>Trial Registration:</bold> This study was registered with the University Hospital Medical Information Network on June 26, 2012 (Clinical trial number: UMIN000011525, URL: <ext-link>https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000013482</ext-link>).

DOI： 10.3389/fcvm.2021.668059

Adipocyte-Specific Inhibition of Mir221/222 Ameliorates Diet-Induced Obesity Through Targeting Ddit4. 査読国際誌

Satoshi Yamaguchi, Dongxiao Zhang, Akihiro Katayama, Naoko Kurooka, Ryosuke Sugawara, Haya Hamed Hassan Albuayjan, Atsuko Nakatsuka, Jun Eguchi, Jun Wada

Frontiers in endocrinology 12 750261 - 750261 2021年

記述言語：英語掲載種別：研究論文（学術雑誌）

MicroRNAs expressed in adipocytes are involved in transcriptional regulation of target mRNAs in obesity, but miRNAs critically involved in this process is not well characterized. Here, we identified upregulation of miR-221-3p and miR-222-3p in the white adipose tissues in C57BL/6 mice fed with high fat-high sucrose (HFHS) chow by RNA sequencing. Mir221 and Mir222 are paralogous genes and share the common seed sequence and Mir221/222AdipoKO mice fed with HFHS chow demonstrated resistance to the development of obesity compared with Mir221/222flox/y . Ddit4 is a direct target of Mir221 and Mir222, and the upregulation of Ddit4 in Mir221/222AdipoKO was associated with the suppression of TSC2 (tuberous sclerosis complex 2)/mammalian target of rapamycin complex 1 (mTORC1)/S6K (ribosomal protein S6 kinase) pathway. The overexpression of miR-222-3p linked to enhanced adipogenesis, and it may be a potential candidate for miRNA-based therapy.

DOI： 10.3389/fendo.2021.750261

Current diagnosis and management of primary chylomicronemia

Hiroaki Okazaki, Takanari Gotoda, Masatsune Ogura, Shun Ishibashi, Kyoko Inagaki, Hiroyuki Daida, Toshio Hayashi, Mika Hori, Daisaku Masuda, Kota Matsuki, Shinji Yokoyama, Mariko Harada-Shiba, Hitoshi Shimano, Koutaro Yokote, Hideaki Bujo, Shizuya Yamashita, Kazuhisa Tsukamoto, Katsunori Ikewaki, Kazushige Dobashi, Yoshihiro Miyamoto, Misa Takegami, Yoshiki Sekijima, Yasushi Ishigaki, Atsushi Nohara, Shingo Koyama, Koh Ono, Masahiro Koseki, Manabu Takahashi, Kimitoshi Nakamura, Takashi Miida, Masa Aki Kawashiri, Tetsuo Minamino, Sachiko Okazaki, Hayato Tada, Jun Wada, Hirotoshi Ohmura, Masashi Yamamoto, Yasuo Takeuchi, Atsuko Nakatsuka, Satoshi Hirayama, Masayuki Kuroda, Takashi Yamaguchi, Takeyoshi Murano

Journal of Atherosclerosis and Thrombosis 28 ( 9 ) 883 - 904 2021年

掲載種別：研究論文（学術雑誌）

Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher. PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-offunction mutations in LPL pathway genes (LPL, LMF1, GPIHBP1, APOC2, and APOA5). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG). The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive. The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life. Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease. Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options.

DOI： 10.5551/jat.RV17054

Dysfunction of CD8 + PD-1 + T cells in type 2 diabetes caused by the impairment of metabolism-immune axis 国際誌

Ichiro Nojima, Shingo Eikawa, Nahoko Tomonobu, Yoshiko Hada, Nobuo Kajitani, Sanae Teshigawara, Satoshi Miyamoto, Atsuhito Tone, Haruhito A. Uchida, Atsuko Nakatsuka, Jun Eguchi, Kenichi Shikata, Heiichiro Udono, Jun Wada

Scientific Reports 10 ( 1 ) 14928 - 14928 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

<title>Abstract</title>
The metabolic changes and dysfunction in CD8 + T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In C57BL/6JJcl mice fed with high fat-high sucrose chow (HFS), multifunctionality of CD8 + splenic and tumor-infiltrating lymphocytes (TILs) was impaired and associated with enhanced tumor growth, which were inhibited by metformin. In CD8 + splenic T cells from the HFS mice, glycolysis/basal respiration ratio was significantly reduced and reversed by metformin. In the patients with T2D (DM), multifunctionality of circulating CD8 + PD-1 + T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality. Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The disturbance of the link between metabolism and immune function in CD8 + PD-1 + T cells in T2D was proved by recovery of antigen-specific and non-specific cytokine production via metformin-mediated increase in glycolytic activity.

DOI： 10.1038/s41598-020-71946-3

その他リンク： http://www.nature.com/articles/s41598-020-71946-3

High expression of a vascular stricture‐related marker is predictive of an early response to tolvaptan, and a low fractional excretion of sodium is predictive of a poor long‐term survival after tolvaptan administration for liver cirrhosis 国際誌

Takuya Adachi, Akinobu Takaki, Shuichi Sato, Hiroshi Tobita, Haruhiko Kobashi, Masaru Kinomura, Atsuko Nakatsuka, Atsushi Oyama, Nozomu Wada, Masahiro Sakata, Yasuto Takeuchi, Tetsuya Yasunaka, Hideki Onishi, Hidenori Shiraha, Hiroyuki Okada

Hepatology Research 50 ( 12 ) 1347 - 1354 2020年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley

AIM: Tolvaptan is a newly available diuretic that has a specific function in water reabsorption inhibition. Given that spironolactone or furosemide induces the aggravation of cirrhotic hyponatremia and dehydration, tolvaptan affects the management strategy of liver cirrhosis. Representative predictive markers of its response include renal function-related markers such as urea nitrogen or creatinine. However, vascular function-related markers have not been well investigated. We investigated the effect of the vascular function-related marker asymmetric dimethylarginine (ADMA) and the effective arterial blood volume (EABV) marker, fractional excretion of sodium (FENa), on the early tolvaptan response and survival in liver cirrhosis. METHODS: We prospectively recruited 49 patients who required add-on tolvaptan for refractory ascites or edema. Laboratory data were obtained immediately before and 1 day after tolvaptan administration. Patients exhibiting >1.5 kg weight loss after 1 week were categorized as early responders to tolvaptan. Patients were followed for a median of 200 days and were assessed for survival. RESULTS: Early responders showed lower creatinine levels (<1.0 mg/dL), and higher ADMA levels (≥0.61 nmol/mL) than others in a multivariate analysis. Patients with a shorter survival were positive for hepatocellular carcinoma and had a low FENa (<0.35%). CONCLUSION: Early responders showed higher ADMA levels reflecting vascular stricture, suggesting that higher vascular tonus is required for a tolvaptan early response. Patients with a shorter survival showed a lower FENa, reflecting a lower EABV and suggesting that adequate EABV is required for the prolonged survival after tolvaptan administration.

DOI： 10.1111/hepr.13573

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/hepr.13573

当院における糖尿病性腎症の進展抑制を目指した取り組み

長田麻里, 片山晶博, 大橋睦子, 高橋絢子, 庄野三友紀, 江口潤, 中司敦子, 宮本聡, 長谷川祐子, 和田淳

糖尿病 63 ( 9 ) 650 - 650 2020年9月

当院におけるTime-In-Range(TIR)とHbA1cとの関連についての検討

片山晶博, 野島一郎, 樋口千草, 渡邉真由, 宮本聡, 中司敦子, 江口潤, 四方賢一, 和田淳

糖尿病 63 ( Suppl.1 ) S - 220 2020年8月

尿細管間質障害におけるHSPA1Lの意義

中司敦子, 江口潤, 和田淳

日本腎臓学会誌 62 ( 4 ) 284 - 284 2020年7月

The hypoglycemia-prevention effect of sensor-augmented pump therapy with predictive low glucose management in Japanese patients with type 1 diabetes mellitus: a short-term study

Akihiro Katayama, Atsuhito Tone, Mayu Watanabe, Sanae Teshigawara, Satoshi Miyamoto, Jun Eguchi, Atsuko Nakatsuka, Kenichi Shikata, Jun Wada

Diabetology International 11 ( 2 ) 97 - 104 2020年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Aims/introduction: The predictive low glucose management (PLGM) system was introduced in March 2018 in Japan. Although there are some reports demonstrating the benefit of PLGM in preventing hypoglycemia, no data are currently available in Japanese patients with type 1 diabetes mellitus (T1DM). The aim of the present study is to evaluate the effect of PLGM with sensor-augmented pump therapy in the prevention of hypoglycemia in Japanese patients. Materials and methods: We included 16 patients with T1DM who used the MiniMed®640G system after switching from the MiniMed®620G system. We retrospectively analysed the data of the continuous glucose monitoring system in 1 month after switching to MiniMed®640G. Results: The area under the curve (AUC) of hypoglycemia of < 70 mg/dL was lowered from 0.42 ± 0.43 mg/dL day to 0.18 ± 0.18 mg/dL day (P = 0.012). Correspondingly, the duration of severe hypoglycemia (< 54 mg/dL) was reduced significantly from 15.3 ± 21.7 min/day to 4.8 ± 6.9 min/day (P = 0.019). The duration of hypoglycemia was reduced, but the reduction was not significant. Regarding the AUC for hyperglycemia > 180 mg/dL and the duration of hyperglycemia did not change. With the PLGM function, 79.3% of the predicted hypoglycemic events were avoided. Conclusions: The hypoglycemia avoidance rate was comparable to those in previous reports. In addition, we demonstrated that PLGM can markedly suppress severe hypoglycemia without deteriorating glycemic control in Japanese T1DM patients. It is necessary to further investigate the effective use of the PLGM feature such as establishing a lower limit and the timing of resumption.

DOI： 10.1007/s13340-019-00408-7

その他リンク： http://link.springer.com/article/10.1007/s13340-019-00408-7/fulltext.html

脂質異常症難病のすべてがわかる! 低HDL-C血症の診断の進め方 LCAT欠損症とタンジール病

武城英明, 小関正博, 黒田正幸, 村野武義, 中司敦子, 和田淳, 竹内康雄, 石川耕, 横手幸太郎, 山下静也

日本動脈硬化学会総会プログラム・抄録集 51回 S12 - 4 2019年7月

Fetuin-Aの糖尿病腎症進展における役割

三瀬広記, 中司敦子, 山口哲志, 勅使川原早苗, 田邊克幸, 江口潤, 和田淳

糖尿病 62 ( Suppl.1 ) S - 202 2019年4月

2型糖尿病患者における尿中糖鎖排泄量と腎・心血管イベントおよび総死亡との関連の検討査読

今村麻理子, 三瀬広記, 中塔辰明, 清水一紀, 安藤晋一郎, 松岡孝, 宮下雄博, 肥田和之, 江口潤, 中司敦子, 四方賢一, 和田淳

糖尿病 62 ( 2 ) 113 - 113 2019年2月

GPIHBP1 autoantibody syndrome during interferon β1a treatment. 査読

Eguchi J, Miyashita K, Fukamachi I, Nakajima K, Murakami M, Kawahara Y, Yamashita T, Ohta Y, Abe K, Nakatsuka A, Mino M, Takase S, Okazaki H, Hegele RA, Ploug M, Hu X, Wada J, Young SG, Beigneux AP

Journal of clinical lipidology 13 ( 1 ) 62 - 69 2019年1月

A retrospective observational study on the effects of switching from conventional insulin pump to sensor-augmented pump (SAP) therapy

Satoshi Yamaguchi, Atsuhito Tone, Sanae Teshigawara, Mayu Watanabe, Akihiro Katayama, Satoshi Miyamoto, Jun Eguchi, Atsuko Nakatsuka, Chigusa Higuchi, Daisuke Ogawa, Kenichi Shikata, Jun Wada

Journal of the Japan Diabetes Society 62 ( 5 ) 315 - 321 2019年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Japan Diabetes Society

The purpose of this retrospective observational study is to analyze the clinical course of sensor augmented pump (SAP) therapy after switching from insulin pump therapy and to evaluate the predictors of the therapeutic effects of SAP therapy. Twenty-two type 1 diabetes patients who received SAP therapy for more than one year after switching from insulin pump therapy were enrolled. HbAlc levels were unchanged at 6 months and significantly improved at 12 months. The HbAlc levels at 6 months were decreased in 14 patients and unchanged or increased in the other 8 patients. In the latter group with unchanged or increased HbAlc levels at 6 months, the mean HbAlc level at the induction of SAP therapy was significantly lower and the percentage of patients with SMBG &lt
70 mg/dL before SAP therapy was higher in comparison to the former group. A multiple regression analysis showed a significant negative correlation between the change in % TBD (6M) and the change in the HbAlc level (6M). Conclusively, in patients with frequent hypoglycemia, we should evaluate the therapeutic effects based on various parameters, such as average sensor glucose levels and AUC &lt
70 mg/dL, since it is possible that the HbAlc level may transiently increase after the induction of SAP therapy in such cases.

DOI： 10.11213/tonyobyo.62.315

Acquired partial lipoatrophy as graft-versus-host disease and treatment with metreleptin: two case reports. 査読国際誌

Shibata Y, Nakatsuka A, Eguchi J, Miyamoto S, Masuda Y, Awazawa M, Takaki A, Yoshida R, Yagi T, Wada J

Journal of medical case reports 12 ( 1 ) 368 - 368 2018年12月

Identification of Novel Urinary Biomarkers for Predicting Renal Prognosis in Patients With Type 2 Diabetes by Glycan Profiling in a Multicenter Prospective Cohort Study: U-CARE Study 1. 査読国際誌

Mise K, Imamura M, Yamaguchi S, Teshigawara S, Tone A, Uchida HA, Eguchi J, Nakatsuka A, Ogawa D, Yoshida M, Yamada M, Shikata K, Wada J

Diabetes care 41 ( 8 ) 1765 - 1775 2018年8月

岡山大学病院における肥満外科治療の導入

香川俊輔, 黒田新士, 菊地覚次, 桑田和也, 西崎正彦, 利根淳仁, 中司敦子, 江口潤, 和田淳, 小林求, 藤原俊義

日本肥満症治療学会学術集会プログラム・抄録集 36回 129 - 129 2018年6月

1型糖尿病合併妊婦における妊娠期間中の体重変化とインスリン所要量の検討

勅使川原早苗, 利根淳仁, 山口哲志, 渡邉真由, 三瀬広記, 野島一郎, 高橋寛子, 柴田祐介, 中司敦子, 江口潤, 和田淳

糖尿病 61 ( Suppl.1 ) S - 311 2018年4月

肥満・糖尿病による近位尿細管細胞障害とvaspinの細胞保護作用機序の解明

中司敦子, 山口哲志, 柴田祐助, 高橋寛子, 三瀬広記, 勅使川原早苗, 江口潤, 和田淳

糖尿病 60 ( Suppl.1 ) S - 259 2017年4月

Serum-inducible protein (IP)-10 is a disease progression-related marker for non-alcoholic fatty liver disease 査読

Nozomu Wada, Akinobu Takaki, Fusao Ikeda, Tetsuya Yasunaka, Masahiro Onji, Kazuhiro Nouso, Atsuko Nakatsuka, Jun Wada, Kazuko Koike, Koji Miyahara, Hidenori Shiraha, Kazuhide Yamamoto, Hiroyuki Okada

HEPATOLOGY INTERNATIONAL 11 ( 1 ) 115 - 124 2017年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

The molecular pathogenesis of non-alcoholic steatohepatitis (NASH) is not well defined. The objective of the present study was to identify disease progression-related cytokines and investigate the molecular pathogenesis of such changes in NASH.
A study population of 20 non-alcoholic fatty liver (NAFL) and 59 NASH patients diagnosed by liver biopsy and 15 healthy volunteers was recruited. The serum pro- and anti-inflammatory cytokines were measured by a multiple enzyme-linked immunosorbent assay. The hepatic mRNA expressions of cytokines were measured by real-time PCR. A monocyte cell line was stimulated with Toll-like receptor (TLR) ligand under a high glucose and insulin condition, and cellular cytokine mRNA expression was quantified.
One group of cytokines was higher in NAFL and NASH than in controls, while another group was higher in NASH than in NAFL and controls. The NASH-specific second group included interleukin (IL)-15 and interferon-gamma-inducible protein (IP)-10. In particular, IP-10 was higher in NAFL than in controls and higher in NASH than in NAFL and controls. The sensitivity to diagnose NASH was 90%, with specificity of 50%. Insulin resistance reflecting a high glucose and insulin condition resulted in higher IP-10 mRNA expression in the monocyte cell line only with concomitant TLR-2 stimulation.
IP-10 is a sensitive marker of the need for liver biopsy. Insulin resistance with bacteria-related TLR-2 stimulation might induce IP-10 production from monocytes. Insulin resistance and intestinal barrier function should be intensively controlled to prevent progression from NAFL to NASH.

DOI： 10.1007/s12072-016-9773-y

Microinflammation and organelle dysfunctions in diabetic nephropathy. 査読

Nakatsuka A, Wada J

Nihon Jinzo Gakkai shi 59 ( 2 ) 58 - 64 2017年

Mitochondrial Dynamics and Mitochondrial Dysfunction in Diabetes 査読

Jun Wada, Atsuko Nakatsuka

ACTA MEDICA OKAYAMA 70 ( 3 ) 151 - 158 2016年6月

記述言語：英語出版者・発行元：OKAYAMA UNIV MED SCHOOL

The mitochondria are involved in active and dynamic processes, such as mitochondrial biogenesis, fission, fusion and mitophagy to maintain mitochondrial and cellular functions. In obesity and type 2 diabetes, impaired oxidation, reduced mitochondrial contents, lowered rates of oxidative phosphorylation and excessive reactive oxygen species (ROS) production have been reported. Mitochondrial biogenesis is regulated by various transcription factors such as peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha), peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and nuclear respiratory factors (NRFs). Mitochondrial fusion is promoted by mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy 1 (OPA1), while fission is governed by the recruitment of dynamin-related protein 1 (DRP1) by adaptor proteins such as mitochondrial fission factor (MFF), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51), and fission 1 (FIS1). Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARKIN promote DRP1-dependent mitochondrial fission, and the outer mitochondrial adaptor MiD51 is required in DRP1 recruitment and PARKIN-dependent mitophagy. This review describes the molecular mechanism of mitochondrial dynamics, its abnormality in diabetes and obesity, and pharmaceuticals targeting mitochondrial biogenesis, fission, fusion and mitophagy.

DOI： 10.18926/AMO/54413

Antiobesity Action of ACAM by Modulating the Dynamics of Cell Adhesion and Actin Polymerization in Adipocytes 査読

Kazutoshi Murakami, Jun Eguchi, Kazuyuki Hida, Atsuko Nakatsuka, Akihiro Katayama, Miwa Sakurai, Haruki Choshi, Masumi Furutani, Daisuke Ogawa, Kohji Takei, Fumio Otsuka, Jun Wada

DIABETES 65 ( 5 ) 1255 - 1267 2016年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER DIABETES ASSOC

Coxsackie virus and adenovirus receptor-like membrane protein (CLMP) was identified as the tight junction-associated transmembrane protein of epithelial cells with homophilic binding activities. CLMP is also recognized as adipocyte adhesion molecule (ACAM), and it is upregulated in mature adipocytes in rodents and humans with obesity. Here, we present that aP2 promoter-driven ACAM transgenic mice are protected from obesity and diabetes with the prominent reduction of adipose tissue mass and smaller size of adipocytes. ACAM is abundantly expressed on plasma membrane of mature adipocytes and associated with formation of phalloidin-positive polymerized form of cortical actin (F-actin). By electron microscopy, the structure of zonula adherens with an intercellular space of approximate to 10-20 nm was observed with strict parallelism of the adjoining cell membranes over distances of 1-20 m, where ACAM and -actin are abundantly expressed. The formation of zonula adherens may increase the mechanical strength, inhibit the adipocyte hypertrophy, and improve the insulin sensitivity.

DOI： 10.2337/db15-1304

糖尿病性腎症におけるVaspinの意義

中司敦子, 三瀬広記, 江口潤, 和田淳

日本腎臓学会誌 58 ( 3 ) 262 - 262 2016年5月

Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis 査読

Atsuko Nakatsuka, Makoto Matsuyama, Satoshi Yamaguchi, Akihiro Katayama, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Daisuke Ogawa, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Eijiro Watanabe, Jun Wada

SCIENTIFIC REPORTS 6 21721 2016年2月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt-/-mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt-/-mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4 alpha resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.

DOI： 10.1038/srep21721

Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis 査読

Akihiro Katayama, Atsuko Nakatsuka, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Motoko Kanzaki, Tomokazu Nunoue, Kazuyuki Hida, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Kazuhide Yamamoto, Hiroshi Kiyonari, Hirofumi Makino, Jun Wada

SCIENTIFIC REPORTS 5 16920 2015年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATURE PUBLISHING GROUP

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity.

DOI： 10.1038/srep16920

Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes 査読

Yu Wang, Akihiro Katayama, Takahiro Terami, Xiaoying Han, Tomokazu Nunoue, Dongxiao Zhang, Sanae Teshigawara, Jun Eguchi, Atsuko Nakatsuka, Kazutoshi Murakami, Daisuke Ogawa, Yasuhide Furuta, Hirofumi Makino, Jun Wada

METABOLISM-CLINICAL AND EXPERIMENTAL 64 ( 6 ) 677 - 688 2015年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：W B SAUNDERS CO-ELSEVIER INC

Objective. In obesity and type 2 diabetes, the impairment of mitochondrial function in white adipose tissue (WAT) is linked to a reduction in whole body insulin sensitivity. Timm44 is upregulated in the kidneys of streptozotocin-induced diabetic mice. In the inner mitochondrial membrane, Timm44 anchors mitochondrial heat-shock protein 70 (mtHsp70) to the translocase of inner mitochondrial membrane 23 (TIM23) complex and facilitates the import of mitochondria-targeted preproteins into the mitochondrial matrix dependent on the inner membrane potential and ATP hydrolysis on ATPase domain of mtHsp70.
Methods. We generated the aP2-promoter driven Timm44 transgenic (Tg) mouse model and investigated whether Timm44 Tg mice fed high-fat/high-sucrose (HFHS) chow are protected from type 2 diabetes and obesity.
Results. The body weight of aP2-promoter driven Timm44 Tg mice was lower than that of wild type mice, and insulin sensitivity was greater in Timm44 Tg mice than in wild type mice. Although WAT weight was not altered in Timm44 Tg mice fed HFHS chow, adipocyte size was reduced, and mitochondrial fusion associated with decreased expression of fission genes, such as Dnm11 and Fis1, was observed. In addition, when fed standard (STD) chow, the expressions of the fusion genes Opal, Mfn1 and Mfn2, and Mfn1 were significantly increased in Timm44 Tg mice compared to wild type mice, and fused mitochondria were also observed in Timm44 Tg mice fed STD chow.
Conclusions. The Timm44 gene may be a new target for the treatment of type 2 diabetes. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.metabol.2015.02.004

Identification of Circulating miR-101, miR-375 and miR-802 as Biomarkers for Type 2 Diabetes 査読

Chigusa Higuchi, Atsuko Nakatsuka, Jun Eguchi, Sanae Teshigawara, Motoko Kanzaki, Akihiro Katayama, Satoshi Yamaguchi, Naoto Takahashi, Kazutoshi Murakami, Daisuke Ogawa, Sakiko Sasaki, Hirofumi Makino, Jun Wada

METABOLISM-CLINICAL AND EXPERIMENTAL 64 ( 4 ) 489 - 497 2015年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：W B SAUNDERS CO-ELSEVIER INC

Purpose. The unique circulating microRNAs (miRNAs) observed in patients with type 2 diabetes (T2D) are candidates as new biomarkers and therapeutic targets. In order to identify circulating miRNAs relevant to the disease process in case of type 2 diabetes, we performed the Illumina sequencing of miRNAs derived from the serum, liver and epididymal white adipose tissue (WAT) of diet-induced obese male C57BL/6J mice.
Basic Procedures. We selected four miRNAs, miR-101, miR-335, miR-375, and miR-802, which are increased in the sera and tissues of obese mice, and measured the serum levels of miRNAs in T2D and subjects with normal glucose tolerance (NGT).
Main Findings. The serum concentrations of miRNAs, log10miR-101, log(10)miR-375, and log(10)miR-802, were significantly increased in the T2D patients compared with NGT subjects (1.41 +/- 2.01 u.s. -0.57 +/- 1.05 (P = 1.36 x 10(-5)), 0.20 +/- 0.58 v.s. 0.038 +/- 1.00 (P = 3.06 x 10(-6)), and 2.45 +/- 1.27 u.s. 0.97 +/- 0.98 (P = 0.014), respectively). The log(10)miR-335 values did not demonstrate any significant differences between the T2D and NGT groups (-1.08 +/- 1.35 v.s. 0.38 +/- 1.21 (P = 0.25)). According to the stepwise regression analysis, the HbA1c was an independent predictor of miR-101. Regarding the serum miR-802 levels, eGFR, HbA1c and HDL-C values were identified as significant determinants.
Principal Conclusions. The present findings demonstrated that the circulating miR-101, miR-375 and miR-802 levels are significantly increased in T2D patients versus NGT subjects and they may become the new biomarkers for type 2 diabetes. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.metabol.2014.12.003

Long-Term Treatment with the Sodium Glucose Cotransporter 2 Inhibitor, Dapagliflozin, Ameliorates Glucose Homeostasis and Diabetic Nephropathy in db/db Mice 査読

Naoto Terami, Daisuke Ogawa, Hiromi Tachibana, Takashi Hatanaka, Jun Wada, Atsuko Nakatsuka, Jun Eguchi, Chikage Sato Horiguchi, Naoko Nishii, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

PLOS ONE 9 ( 6 ) e100777 2014年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been reported as a new therapeutic strategy for treating diabetes. However, the effect of SGLT2 inhibitors on the kidney is unknown. In addition, whether SGLT2 inhibitors have an anti-inflammatory or antioxidative stress effect is still unclear. In this study, to resolve these issues, we evaluated the effects of the SGLT2 inhibitor, dapagliflozin, using a mouse model of type 2 diabetes and cultured proximal tubular epithelial (mProx24) cells. Male db/db mice were administered 0.1 or 1.0 mg/kg of dapagliflozin for 12 weeks. Body weight, blood pressure, blood glucose, hemoglobin A1c, albuminuria and creatinine clearance were measured. Mesangial matrix accumulation and interstitial fibrosis in the kidney and pancreatic beta-cell mass were evaluated by histological analysis. Furthermore, gene expression of inflammatory mediators, such as osteopontin, monocyte chemoattractant protein-1 and transforming growth factor-beta, was evaluated by quantitative reverse transcriptase-PCR. In addition, oxidative stress was evaluated by dihydroethidium and NADPH oxidase 4 staining. Administration of 0.1 or 1.0 mg/kg of dapagliflozin ameliorated hyperglycemia, beta-cell damage and albuminuria in db/db mice. Serum creatinine, creatinine clearance and blood pressure were not affected by administration of dapagliflozin, but glomerular mesangial expansion and interstitial fibrosis were suppressed in a dose-dependent manner. Dapagliflozin treatment markedly decreased macrophage infiltration and the gene expression of inflammation and oxidative stress in the kidney of db/db mice. Moreover, dapagliflozin suppressed the high-glucose-induced gene expression of inflammatory cytokines and oxidative stress in cultured mProx24 cells. These data suggest that dapagliflozin ameliorates diabetic nephropathy by improving hyperglycemia along with inhibiting inflammation and oxidative stress.

DOI： 10.1371/journal.pone.0100777

Serum vaspin levels are associated with physical activity or physical fitness in Japanese: a pilot study 査読

Nobuyuki Miyatake, Jun Wada, Atsuko Nakatsuka, Noriko Sakano, Sanae Teshigawara, Motohiko Miyachi, Izumi Tabata, Takeyuki Numata

ENVIRONMENTAL HEALTH AND PREVENTIVE MEDICINE 19 ( 3 ) 200 - 206 2014年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

To investigate the link between serum vaspin levels and physical activity and/or physical fitness in Japanese.
A total of 156 subjects (81 men and 75 women) was enrolled in this cross-sectional study. Serum vaspin levels, physical activity by uniaxial accelerometers, peak oxygen uptake, and metabolic risk parameters were evaluated. We also assessed anthropometric and body composition parameters.
Serum vaspin levels were over the level of 10 ng/mL in 15 subjects (9.6 %: Vaspin High group). In Vaspin Low group (< 5 ng/mL: 74 men and 67 women), serum vaspin levels were 0.12 +/- A 0.18 ng/mL in men and 0.39 +/- A 0.70 ng/mL in women. Peak oxygen uptake was significantly and positively correlated with serum vaspin levels even after adjusting for age, physical activity evaluated by I [metabolic pound equivalents x h per week (METsa <...h/w)], BMI, and other confounding factors in men. In turn, physical activity was significantly and positively correlated with serum vaspin levels even after adjusting for confounding factors in women.
Serum vaspin levels were closely associated with physical fitness in men and physical activity in women independent of body composition in this Japanese cohort.

DOI： 10.1007/s12199-013-0375-1

Pemt Deficiency Ameliorates Endoplasmic Reticulum Stress in Diabetic Nephropathy 査読

Mayu Watanabe, Atsuko Nakatsuka, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Chigusa Higuchi, Akihiro Katayama, Sanae Teshigawara, Jun Eguchi, Daisuke Ogawa, Eijiro Watanabe, Jun Wada, Hirofumi Makino

PLOS ONE 9 ( 3 ) e92647 2014年3月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Phosphatidylethanolamine N-methyltransferase (Pemt) catalyzes the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) mainly in the liver. Under an obese state, the upregulation of Pemt induces endoplasmic reticulum (ER) stress by increasing the PC/PE ratio in the liver. We targeted the Pemt gene in mice to explore the therapeutic impact of Pemt on the progression of diabetic nephropathy and diabetes, which was induced by the injection of streptozotocin (STZ). Although the blood glucose levels were similar in STZ-induced diabetic Pemt+/+ and Pemt-/-mice, the glomerular hypertrophy and albuminuria in Pemt-/- mice were significantly reduced. Pemt deficiency reduced the intraglomerular F4/80-positive macrophages, hydroethidine fluorescence, tubulointerstitial fibrosis and tubular atrophy. The expression of glucose-regulated protein-78 (GRP78) was enriched in the renal tubular cells in STZ-induced diabetic mice, and this was ameliorated by Pemt deficiency. In mProx24 renal proximal tubular cells, the treatment with ER-stress inducers, tunicamycin and thapsigargin, increased the expression of GRP78, which was reduced by transfection of a shRNA lentivirus for Pemt (shRNA-Pemt). The number of apoptotic cells in the renal tubules was significantly reduced in Pemt-/- diabetic mice, and shRNA-Pemt upregulated the phosphorylation of Akt and decreased the cleavage of caspase 3 and 7 in mProx24 cells. Taken together, these findings indicate that the inhibition of Pemt activity ameliorates the ER stress associated with diabetic nephropathy in a model of type 1 diabetes and corrects the functions of the three major pathways downstream of ER stress, i.e. oxidative stress, inflammation and apoptosis.

DOI： 10.1371/journal.pone.0092647

Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice 査読

Hiromi Tachibana, Daisuke Ogawa, Norio Sogawa, Masato Asanuma, Ikuko Miyazaki, Naoto Terami, Takashi Hatanaka, Chikage Sato Horiguchi, Atsuko Nakatsuka, Jun Eguchi, Jun Wada, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

American Journal of Physiology - Renal Physiology 306 ( 1 ) F105 - F115 2014年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney
however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT-/-) and MT+/+ mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT-/- mice compared with diabetic MT+/+ mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT-/- mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy. © 2014 the American Physiological Society.

DOI： 10.1152/ajprenal.00034.2013

Nuclear Hormone Receptor Expression in Mouse Kidney and Renal Cell Lines 査読

Daisuke Ogawa, Jun Eguchi, Jun Wada, Naoto Terami, Takashi Hatanaka, Hiromi Tachibana, Atsuko Nakatsuka, Chikage Sato Horiguchi, Naoko Nishii, Hirofumi Makino

PLOS ONE 9 ( 1 ) e85594 2014年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Nuclear hormone receptors (NHRs) are transcription factors that regulate carbohydrate and lipid metabolism, immune responses, and inflammation. Although several NHRs, including peroxisome proliferator-activated receptor-gamma (PPAR gamma) and PPAR alpha, demonstrate a renoprotective effect in the context of diabetic nephropathy (DN), the expression and role of other NHRs in the kidney are still unrecognized. To investigate potential roles of NHRs in the biology of the kidney, we used quantitative real-time polymerase chain reaction to profile the expression of all 49 members of the mouse NHR superfamily in mouse kidney tissue (C57BL/6 and db/m), and cell lines of mesangial (MES13), podocyte (MPC), proximal tubular epithelial (mProx24) and collecting duct (mIMCD3) origins in both normal and high-glucose conditions. In C57BL/6 mouse kidney cells, hepatocyte nuclear factor 4 alpha, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and COUP-TFIII were highly expressed. During hyperglycemia, the expression of the NHR 4A subgroup including neuron-derived clone 77 (Nur77), nuclear receptor-related factor 1, and neuron-derived orphan receptor 1 significantly increased in diabetic C57BL/6 and db/db mice. In renal cell lines, PPAR delta was highly expressed in mesangial and proximal tubular epithelial cells, while COUP-TFs were highly expressed in podocytes, proximal tubular epithelial cells, and collecting duct cells. High-glucose conditions increased the expression of Nur77 in mesangial and collecting duct cells, and liver x receptor alpha in podocytes. These data demonstrate NHR expression in mouse kidney cells and cultured renal cell lines and suggest potential therapeutic targets in the kidney for the treatment of DN.

DOI： 10.1371/journal.pone.0085594

Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice 査読

Hiromi Tachibana, Daisuke Ogawa, Norio Sogawa, Masato Asanuma, Ikuko Miyazaki, Naoto Terami, Takashi Hatanaka, Chikage Sato Horiguchi, Atsuko Nakatsuka, Jun Eguchi, Jun Wada, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY 306 ( 1 ) F105 - F115 2014年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER PHYSIOLOGICAL SOC

Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney; however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT-/-) and MT+/+ mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT-/- mice compared with diabetic MT+/+ mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT-/- mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy.

DOI： 10.1152/ajprenal.00034.2013

Comparison of Incubation Solutions Prior to the Purification of Porcine Islet Cells. 査読国際誌

Kawai T, Noguchi H, Kuise T, Nakatsuka A, Katayama A, Imagawa N, Kataoka HU, Saitoh I, Noguchi Y, Watanabe M, Fujiwara T

Cell medicine 6 ( 1-2 ) 9 - 14 2013年12月

Comparison of New Preservation Solutions, HN-1 and University of Wisconsin Solution, in Pancreas Preservation for Porcine Islet Isolation. 査読国際誌

Katayama A, Noguchi H, Kuise T, Nakatsuka A, Hirota D, Kataoka HU, Kawai T, Inoue K, Imagawa N, Saitoh I, Noguchi Y, Watanabe M, Wada J, Fujiwara T

Cell medicine 6 ( 1-2 ) 3 - 8 2013年12月

Urinary angiotensinogen is a marker for tubular injuries in patients with type 2 diabetes 査読

Takahiro Terami, Jun Wada, Kentaro Inoue, Atsuko Nakatsuka, Daisuke Ogawa, Sanae Teshigawara, Kazutoshi Murakami, Akihiro Katayama, Jun Eguchi, Hirofumi Makino

International Journal of Nephrology and Renovascular Disease 6 233 - 240 2013年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Purpose: Urinary angiotensinogen has been reported as a marker for the activation of intrarenal renin-angiotensin system (RAS) in various kidney diseases. To investigate the importance of urinary angiotensinogen in diabetic nephropathy, we compared the urinary levels of angiotensinogen, albumin, and α1-microglobulin. Materials and methods: Japanese patients with type 2 diabetes at various stages of nephropathy (n=85) were enrolled, and we measured albumin/creatinine ratio (ACR) and urinary excretion of angiotensinogen and α1-microglobulin. We also compared the clinical data of the patients treated with or without angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (RAS inhibitors [+], n=51
RAS inhibitors [-], n=34). Results: Urinary angiotensinogen levels positively correlated with ACR (r =0.367, P=3.84×10-4) and urinary α1-microglobulin (r=0.734, P=1.32 × 10-15), while they negatively correlated with estimated glomerular filtration ratio (eGFR) (r=-0.350, P=1.02 × 10-3) and high-density lipoprotein cholesterol (r=-0.216, P=0.049). Multiple regression analysis was carried out to predict urinary angiotensinogen levels by employing eGFR, ACR, and urinary α1-microglobulin as independent variables
only urinary α1-microglobulin entered the regression equation at a significant level. Although ACR was higher in the RAS inhibitors (+) group, urinary α1-microglobulin and angiotensinogen did not show significant increase in the RAS inhibitors (+) group. Conclusion: Urinary angiotensinogen is well correlated with urinary α1-microglobulin and reflected the tubular injuries which may be associated with the intrarenal RAS activation in patients with type 2 diabetes. © 2013 Terami et al.

DOI： 10.2147/IJNRD.S51829

Urinary Fetuin-A Is a Novel Marker for Diabetic Nephropathy in Type 2 Diabetes Identified by Lectin Microarray 査読

Kentaro Inoue, Jun Wada, Jun Eguchi, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Daisuke Ogawa, Takahiro Terami, Akihiro Katayama, Atsuhito Tone, Izumi Iseda, Kazuyuki Hida, Masao Yamada, Tomohisa Ogawa, Hirofumi Makino

PLoS ONE 8 ( 10 ) e77118 2013年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

We analyzed the urine samples of patients with type 2 diabetes at various stages of diabetic nephropathy by lectin microarray to identify a biomarker to predict the progression of diabetic nephropathy. Japanese patients with type 2 diabetes at various stages of nephropathy were enrolled and we performed lectin microarray analyses (n = 17) and measured urinary excretion of fetuin-A (n = 85). The increased signals of urine samples were observed in Siaα2-6Gal/GalNAc-binding lectins (SNA, SSA, TJA-I) during the progression of diabetic nephropathy. We next isolated sialylated glycoproteins by using SSA-lectin affinity chromatography and identified fetuin-A by liquid chromatography-tandem mass spectrometer. Urinary excretion of fetuin-A significantly increased during the progression of albuminuria (A1, 0.40±0.43
A2, 0.60±0.53
A3 1.57±1.13 ng/gCr
p = 7.29×10-8) and of GFR stages (G1, 0.39±0.39
G2, 0.49±0.45
G3, 1.25±1.18
G4, 1.34±0.80 ng/gCr
p = 3.89×10-4). Multivariate logistic regression analysis was employed to assess fetuin-A as a risk for diabetic nephropathy with microalbuminuria or GFR&lt
60 mL/min. Fetuin-A is demonstrated as a risk factor for both microalbuminuria and reduction of GFR in diabetic nephropathy with the odds ratio of 4.721 (1.881-11.844) and 3.739 (1.785-7.841), respectively. Collectively, the glycan profiling analysis is useful method to identify the urine biomarkers and fetuin-A is a candidate to predict the progression of diabetic nephropathy. © 2013 Inoue et al.

DOI： 10.1371/journal.pone.0077118

Nuclear Hormone Receptor Expression in Mouse Kidney and Renal Cell Lines

Naoto Terami, Daisuke Ogawa, Jun Eguchi, Hiromi Tachibana, Chikage Sato-Horiguchi, Takashi Hatanaka, Atsuko Nakatsuka, Jun Wada, Hirofumi Makino

DIABETES 62 A134 - A134 2013年7月

Phosphatidylethanolamine N-Methyltransferase (PEMT) Deficiency Protects from Obesity and Insulin Resistance but Promote Steatoheptitis With Tumorigenesis 査読

Atsuko Nakatsuka, Jun Wada, Kazutoshi Murakami, Takahiro Terami, Jun Eguchi, Daisuke Ogawa, Hirofumi Makino

DIABETES 62 A529 - A529 2013年7月

Cell Cycle Abnormality in Metabolic Syndrome and Nuclear Receptors as an Emerging Therapeutic Target 査読

Atsuko Nakatsuka, Jun Wada, Hirofumi Makino

ACTA MEDICA OKAYAMA 67 ( 3 ) 129 - 134 2013年6月

担当区分：筆頭著者記述言語：英語出版者・発行元：OKAYAMA UNIV MED SCHOOL

In recent years, many researchers have emphasized the importance of metabolic syndrome based on its increasing prevalence and its adverse prognosis due to associated chronic vascular complications. Upstream of a cluster of metabolic and vascular disorders is the accumulation of visceral adipose tissue, which plays a central role in the pathophysiology. In the accumulation of adipose tissues, cell cycle regulation is tightly linked to cellular processes such as proliferation, hypertrophy and apoptosis. In addition, various cell cycle abnormalities have also been observed in other tissues, such as kidneys and the cardiovascular system, and they are critically involved in the progression of disease. Here, we discuss cell cycle abnormalities in metabolic syndrome in various tissues. Furthermore, we describe the role of nuclear receptors in cell growth and survival, and glucose and lipid metabolism in the whole body. Therapeutic strategies for modulating various cell cycles in metabolic disorders by targeting nuclear receptors may overcome obesity and its chronic vascular complications in the future.

DOI： 10.18926/AMO/50405

Visceral adipose tissue-derived serine proteinase inhibitor inhibits apoptosis of endothelial cells as a ligand for the cell-surface GRP78/voltage-dependent anion channel complex (vol 112, pg 771, 2013) 査読

A. Nakatsuka, J. Wada, I. Iseda

CIRCULATION RESEARCH 112 ( 9 ) E98 - E98 2013年4月

【内分泌ホルモンのすべて】(第15章)脂肪由来のホルモンバスピン

和田淳, 勅使川原早苗, 中司敦子

内分泌・糖尿病・代謝内科 36 ( Suppl.4 ) 466 - 471 2013年4月

Visceral Adipose Tissue-derived Serine Proteinase Inhibitor Inhibits Apoptosis of Endothelial Cells as a Ligand for the Cell-Surface GRP78/Voltage-dependent Anion Channel Complex 査読

Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino

CIRCULATION RESEARCH 112 ( 5 ) 771 - + 2013年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Rationale: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats.
Objective: The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu.
Methods and Results: Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using 125I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565x10(-9) m) by the treatment of 5 mu M thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca2+ influx and subsequent apoptosis.
Conclusions: Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus. (Circ Res. 2013;112:771-780.)

DOI： 10.1161/CIRCRESAHA.111.300049

Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease 査読

Yuko Kurose, Jun Wada, Motoko Kanzaki, Sanae Teshigawara, Atsuko Nakatsuka, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Mayu Watanabe, Chigusa Higuchi, Jun Eguchi, Nobuyuki Miyatake, Hirofumi Makino

BMC NEPHROLOGY 14 23 2013年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BIOMED CENTRAL LTD

Background: Galectin-9 (Gal-9) induces apoptosis in activated T helper 1 (T(H)1) cells as a ligand for T cell immunoglobulin mucin-3 (Tim-3). Gal-9 also inhibits the G1 phase cell cycle arrest and hypertrophy in db/db mice, the hallmark of early diabetic nephropathy, by reversing the high glucose-induced up-regulation of cyclin dependent kinase inhibitors such as p27(Kip1) and p21(Cip1).
Methods: We investigated the serum levels of Gal-9 in the patients with type 2 diabetes and various stages of chronic kidney disease (CKD) (n = 182).
Results: Serum Gal-9 levels in the patients with type 2 diabetes were 131.9 +/- 105.4 pg/ml and Log(10)Gal-9 levels significantly and positively correlated with age (r = 0.227, p = 0.002), creatinine (r = 0.175, p = 0.018), urea nitrogen (r = 0.162, p = 0.028) and osmotic pressure (r = 0.187, p = 0.014) and negatively correlated with estimated glomerular filtration rate (eGFR) (r = -0.188, p = 0.011). Log(10)Gal-9 levels increased along with the progression of GFR categories of G1 to G4, and they were statistically significant by Jonckheere-Terpstra test (p = 0.012). Log(10)Gal-9 levels remained similar levels in albuminuria stages of A1 to A3.
Conclusion: The elevation of serum Gal-9 in the patients with type 2 diabetes is closely linked to GFR and they may be related to the alteration of the immune response and inflammation of the patients with type 2 diabetes and CKD.

DOI： 10.1186/1471-2369-14-23

The serum vaspin levels are reduced in Japanese chronic hemodialysis patients 査読

Junko Inoue, Jun Wada, Sanae Teshigawara, Kazuyuki Hida, Atsuko Nakatsuka, Yuji Takatori, Shoichirou Kojo, Shigeru Akagi, Kazushi Nakao, Nobuyuki Miyatake, John F. McDonald, Hirofumi Makino

BMC NEPHROLOGY 13 163 2012年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BIOMED CENTRAL LTD

Background: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified in genetically obese rats that correlates with insulin resistance and obesity in humans. Recently, we found that 7% of the Japanese population with the minor allele sequence (A) of rs77060950 exhibit higher levels of serum vaspin. We therefore evaluated the serum vaspin levels in Japanese chronic hemodialysis patients.
Methods: Healthy Japanese control volunteers (control; n = 95, 49.9 +/- 6.91 years) and Japanese patients undergoing hemodialysis therapy (HD; n = 138, 51.4 +/- 10.5 years) were enrolled in this study, and serum samples were subjected to the human vaspin RIA system.
Results: The measurement of the serum vaspin levels demonstrated that a fraction of control subjects (n = 5) and HD patients (n = 11) exhibited much higher levels (> 10 ng/ml; Vaspin(High) group), while the rest of the population exhibited lower levels (< 3 ng/ml; Vaspin(Low) group). By comparing the patients in the Vaspin(Low) group, the serum vaspin levels were found to be significantly higher in the control subjects (0.87 +/- 0.24 ng/ml) than in the HD patients (0.32 +/- 0.15 ng/ml) (p < 0.0001). In the stepwise regression analyses, the serum creatinine and triglyceride levels were found to be independently and significantly associated with the vaspin concentrations in all subjects.
Conclusions: The creatinine levels are negatively correlated with the serum vaspin levels and were significantly reduced in the Japanese HD patients in the Vaspin(Low) group.

DOI： 10.1186/1471-2369-13-163

Vaspin Is an Adipokine Ameliorating ER Stress in Obesity as a Ligand for Cell-Surface GRP78/MTJ-1 Complex 査読

Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Chikage Sato Horiguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino

DIABETES 61 ( 11 ) 2823 - 2832 2012年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER DIABETES ASSOC

It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions. Diabetes 61:2823-2832, 2012

DOI： 10.2337/db12-0232

Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice 査読

Daisuke Kawai, Akinobu Takaki, Atsuko Nakatsuka, Jun Wada, Naofumi Tamaki, Tetsuya Yasunaka, Kazuko Koike, Ryuichiro Tsuzaki, Kazuyuki Matsumoto, Yasuhiro Miyake, Hidenori Shiraha, Manabu Morita, Hirofumi Makino, Kazuhide Yamamoto

HEPATOLOGY 56 ( 3 ) 912 - 921 2012年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-cholinedeficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet + control water (CW group); (2) MCD diet + hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-a, interleukin-6, fatty acid synthesisrelated genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick-end labeling (TUNEL)positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator-activated receptor-a expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups. Conclusion: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis. (HEPATOLOGY 2012;56:912921)

DOI： 10.1002/hep.25782

肥満症におけるGpnmbの意義

片山晶博, 和田淳, 中司敦子, 江口潤, 村上和敏, 神崎資子, 勅使川原早苗, 井上謙太郎, 寺見隆宏, 渡邉真由, 樋口千草, 肥田和之, 四方賢一, 槇野博史

肥満研究 18 ( Suppl. ) 156 - 156 2012年9月

Serum Vaspin Concentrations Are Closely Related to Insulin Resistance, and rs77060950 at SERPINA12 Genetically Defines Distinct Group with Higher Serum Levels in Japanese Population 査読

Sanae Teshigawara, Jun Wada, Kazuyuki Hida, Atsuko Nakatsuka, Jun Eguchi, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Izumi Iseda, Yuichi Matsushita, Nobuyuki Miyatake, John F. McDonald, Kikuko Hotta, Hirofumi Makino

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 97 ( 7 ) E1202 - E1207 2012年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ENDOCRINE SOC

Context: Vaspin is an adipokine with insulin-sensitizing effects identified from visceral adipose tissues of genetically obese rats.
Objective: We investigated genetic and nongenetic factors that define serum concentrations of vaspin.
Design, Setting and Participants: Vaspin levels were measured with RIA in Japanese subjects with normal fasting plasma glucose (NFG; n = 259) and type 2 diabetes patients (T2D; n = 275). Single nucleotide polymorphisms (SNP) at SERPINA12 (vaspin) gene locus were discovered, and five SNP were genotyped in the subjects with varied body mass index (n = 1138).
Results: The level of serum vaspin in 93% of the samples was found to vary from 0.2 to nearly 2 ng/ml in NFG subjects (n = 259) and from 0.2 to nearly 3 ng/ml in T2D patients (n = 275) (Vaspin(Low) group), whereas a significant subpopulation (7%) in both groups displayed much higher levels of 10-40 ng/ml (Vaspin(High) group). In the Vaspin(Low) group, serum vaspin levels in T2D were significantly higher than healthy subjects (0.99 +/- 0.04 vs. 0.86 +/- 0.02 ng/ml; P < 0.01). Both in T2D and genotyped Japanese population, serum vaspin levels closely correlated with homeostasis model of assessment for insulin resistance rather than anthropometric parameters. By genotyping, rs77060950 tightly linked to serum vaspin levels, i.e. CC (0.6 +/- 0.4 ng/ml), CA (18.4 +/- 9.6 ng/ml), and AA (30.5 +/- 5.1 ng/ml) (P < 2 x 10(-16)). Putative GATA-2 and GATA-3 binding consensus site was found at rs77060950.
Conclusions: Serum vaspin levels were related to insulin resistance, and higher levels of serum vaspin in 7% of the Japanese population are closely linked to minor allele sequence (A) of rs77060950. (J Clin Endocrinol Metab 97: E1202-E1207, 2012)

DOI： 10.1210/jc.2011-3297

RXR antagonism induces G0/G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21(Cip1) pathway in adipocytes 査読

Atsuko Nakatsuka, Jun Wada, Kazuyuki Hida, Aya Hida, Jun Eguchi, Sanae Teshigawara, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Daisuke Ogawa, Hiroyuki Kagechika, Hirofumi Makino

JOURNAL OF PATHOLOGY 226 ( 5 ) 784 - 795 2012年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

The peroxisome proliferator activated receptor-gamma (PPAR gamma) agonist, pioglitazone (PIO), exerts anti-diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti-obesity and anti-diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well-investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G(0)/G(1) cell cycle arrest associated with the inhibition of cellular hypertrophy, which resulted in the reduction of fat pad mass. In contrast, PIO promoted proliferation activities associated with the increase in M + late M:G(0) + G(1) ratio and the appearance of both small and hypertrophied adipocytes. In cultured human visceral preadipocytes HX531 up-regulated cell cycle regulators, p53, p21(Cip1), cyclin D1, Fbxw7 and Skp2, which are known contributors towards G(0)/G(1) cell cycle arrest. The knockdown of p53 with a shRNA lentivirus reversed the HX531-induced up-regulation of p21(Cip1), which is one of the major p53-effector molecules. We conclude that HX531 exerts anti-obesity and anti-diabetes properties by up-regulating the p53-p21(Cip1) pathway, resulting in G(0)/G(1) cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/path.3001

Galectin-9 and T Cell Immunoglobulin Mucin-3 Pathway Is a Therapeutic Target for Type 1 Diabetes 査読

Motoko Kanzaki, Jun Wada, Koichi Sugiyama, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Jun Eguchi, Hisaya Akiba, Hideo Yagita, Hirofumi Makino

ENDOCRINOLOGY 153 ( 2 ) 612 - 620 2012年2月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ENDOCRINE SOC

Galectin-9 (Gal-9), a ligand for T cell Ig mucin-3 (Tim-3), induces apoptosis in cluster of differentiation 4 (CD4)(+) Tim-3(+) T helper 1 (T(H)1) cells via the Gal-9-Tim-3 pathway and negatively regulates T(H)1 immunity. In turn, Gal-9 activates dendritic cells (DC) to produce TNF-alpha, which promotes the T(H)1 response. We investigated the efficacy of Gal-9 against T(H)1-mediated autoimmune diabetes in NOD mice and compared with anti-Tim-3 monoclonal antibody (RMT3-23), which inhibited the binding between Tim-3-Ig and Gal-9 in a solid-phase binding assay. mRNA expression of Gal-9 was prominently induced by the treatment of interferon-gamma in MIN6 cells, and Gal-9 was also expressed in the pancreatic beta-cells in NOD mice, suggesting Gal-9 may be released from pancreatic beta-cells to terminate T(H)1-mediated inflammation. Long-term injection of Gal-9 exhibits preventive efficacy for development of diabetes in NOD mice, but RMT3-23 demonstrated further prominent therapeutic potential compared with Gal-9. Gal-9 induced apoptosis of CD4(+)Tim-3(+) T(H)1 cells at the concentration of 0.2 mu M, whereas RMT3-23 failed to enhance the apoptosis of CD4(+)Tim-3(+) T(H)1 cells. In contrast, Gal-9 induced TNF-alpha production in cultured DC in a dose-dependent manner; however, RMT3-23 inhibited Gal-9-induced TNF-alpha production in a dose-dependent manner. Although Gal-9 exhibited certain therapeutic potential against autoimmune diabetes by enhancing apoptosis of CD4(+)Tim-3(+) T(H)1 cells, RMT3-23 exhibited prominent therapeutic efficacy by suppressing the TNF-alpha production and activation of DC. Taken together, the inhibition of the Gal-9-Tim-3 pathway on DC, upstream of T(H)1 response, may be a new target for the treatment of type 1 diabetes. (Endocrinology 153: 612-620, 2012)

DOI： 10.1210/en.2011-1579

Telmisartan attenuates diabetic nephropathy by suppressing oxidative stress in db/db mice. 査読国際誌

Sato-Horiguchi C, Ogawa D, Wada J, Tachibana H, Kodera R, Eguchi J, Nakatsuka A, Terami N, Shikata K, Makino H

Nephron. Experimental nephrology 121 ( 3-4 ) e97 - e108 2012年

A Case of Type 2 Diabetes and Metastatic Liver Cancer Exhibiting Hypercholesterolemia with Abnormal Lipoproteins 査読

Motoko Kanzaki, Jun Wada, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Junichiro Nasu, Kazuhide Yamamoto, Hirofumi Makino

INTERNAL MEDICINE 51 ( 6 ) 619 - 623 2012年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

Although the appearance of abnormal lipoproteins in liver diseases is well known, the precise analyses of abnormal lipoproteins remain elusive. Here, we report a 71-year-old woman with type 2 diabetes whose serum cholesterol levels were elevated to 560 mg/dL over a 4-month period. High-performance liquid chromatography demonstrated the presence of lipoprotein-X and lipoprotein-Y and sigmoid colon cancer and multiple liver metastases were found by colonoscopy and computed tomography. Remission of the primary colon cancer and liver lesions was achieved by chemotherapy with oxaliplatin and fluorouracil and her serum cholesterol went back to basal levels associated with the disappearance of abnormal lipoproteins.

DOI： 10.2169/internalmedicine.51.6486

Telmisartan Attenuates Diabetic Nephropathy by Suppressing Oxidative Stress in db/db Mice 査読

Chikage Sato-Horiguchi, Daisuke Ogawa, Jun Wada, Hiromi Tachibana, Ryo Kodera, Jun Eguchi, Atsuko Nakatsuka, Naoto Terami, Kenichi Shikata, Hirofumi Makino

NEPHRON EXPERIMENTAL NEPHROLOGY 121 ( 3-4 ) E97 - E108 2012年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：KARGER

Background/Aims: Telmisartan, an angiotensin II type 1 receptor blocker, is widely used to treat hypertension and kidney diseases, including diabetic nephropathy, because of its renoprotective effects. However, the mechanism by which telmisartan prevents proteinuria and renal dysfunction in diabetic nephropathy is still unclear. In this study, we examined the effects of telmisartan against diabetic nephropathy in db/db mice. Methods: Telmisartan was administered at a dose of 5 mg/kg/day for 3 weeks to db/db (diabetic) and db/m (control) mice. Urinary albumin excretion, renal histology, and the gene expression of oxidative stress and inflammatory markers in renal tissue were determined. To evaluate the effects of telmisartan on reactive oxygen species (ROS) production, superoxide was detected by dihydroethidium (DHE) staining in vivo and in vitro. Results: Telmisartan reduced albuminuria, mesangial matrix expansion, macrophage infiltration, and the expression of ROS markers (NADPH oxidase 4- and 8-hydroxydeoxyguanosine) and inflammatory cytokines (monocyte chemoattractant protein-1, osteopontin, and transforming growth factor-beta) in the kidney. DHE staining showed that telmisartan decreased ROS generation in the kidney and in cultured mesangial and proximal tubular epithelial cells. Conclusions: Taken together, these findings indicate that telmisartan protects against diabetic nephropathy by reducing diabetes-induced oxidative stress. Copyright (c) 2013 S. Karger AG, Basel

DOI： 10.1159/000343102

Two novel mutations of lecithin:cholesterol acyltransferase (LCAT) gene and the influence of APOE genotypes on clinical manifestations 査読

Akihiro Katayama, Jun Wada, Hitomi Usui Kataoka, Hiroko Yamasaki, Sanae Teshigawara, Takahiro Terami, Kentaro Inoue, Motoko Kanzaki, Kazutoshi Murakami, Atsuko Nakatsuka, Hitoshi Sugiyama, Norio Koide, Hideaki Bujo, Hirofumi Makino

NDT Plus 4 ( 5 ) 299 - 302 2011年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Familial lecithin:cholesterol acyltransferase deficiency (FLD) is an autosomal recessive disorder characterized by corneal opacity, hemolytic anemia, low high-density lipoprotein cholesterol (HDL-C) and proteinuria. Two novel lecithin:cholesterol acyltransferase (LCAT) mutations[c.278 C&gt
T (p.Pro69Leu)
c.950 T&gt
C (p.Met293Thr)] were identified in a 27-year-old man and in a 30-year-old woman, respectively. Both patients manifested corneal opacity, hemolytic anemia, low low-density lipoprotein cholesterol and HDL-C and proteinuria. Lipid deposits with vacuolar lucent appearance in glomerular basement membranes were observed in both cases. APOE genotype was also investigated: the first case results ε4/ε3, the second ε2/ε2
however, they shared a similar phenotype characterized by the presence of intermediate-density lipoproteins (IDL) remnant and the absence of lipoprotein-X. In conclusion, our findings suggest that APOE ε2/ε2 may not be the major determinant gene for the appearance of IDL in FLD patients. © 2011 The Author.

DOI： 10.1093/ndtplus/sfr091

[Obesity: Progress in diagnosis and treatment; Topics, IV. Recent topics: 3. Obesity and new secretory factors; 1) Vaspin]. 査読

Wada J, Teshigawara S, Nakatsuka A, Makino H

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 100 ( 4 ) 996 - 1001 2011年4月

記述言語：日本語出版者・発行元：The Japanese Society of Internal Medicine

バスピン（vaspin）は肥満ラットの内臓脂肪から発見されたアディポサイトカインである．肥満マウスへのリコンビナント蛋白の投与実験から肥満症におけるインスリン抵抗性を改善する代償因子であると考えている．バスピンはヒトの血中にも存在し，肥満症においては体格指数，インスリン抵抗性指数と正相関を認めるとの報告が多い．また2型糖尿病でも血中濃度が増加し，女性で高値である．アディポネクチンやレプチンとは異なった血中濃度動態を示しており肥満症治療の新たな分子ターゲットである．<br>

DOI： 10.2169/naika.100.996

その他リンク： https://jlc.jst.go.jp/DN/JALC/00368341128?from=CiNii

新規脂肪細胞膜蛋白Gpnmbの同定

片山晶博, 和田淳, 中司敦子, 村上和敏, 神崎資子, 勅使川原早苗, 井上謙太郎, 寺見隆宏, 肥田和之, 四方賢一, 槇野博史

糖尿病 54 ( Suppl.1 ) S - 356 2011年4月

ACAMの脂肪分化とメタボリックシンドロームにおける意義

村上和敏, 和田淳, 中司敦子, 神崎資子, 勅使川原早苗, 寺見隆宏, 井上謙太郎, 片山晶博, 四方賢一, 槇野博史

糖尿病 54 ( Suppl.1 ) S - 132 2011年4月

糖尿病性腎症の糖鎖プロファイングの検討

井上謙太郎, 和田淳, 中司敦子, 村上和敏, 神崎資子, 寺見隆宏, 勅使川原早苗, 黒瀬祐子, 片山晶博, 小川智央, 山田雅雄, 四方賢一, 槇野博史

糖尿病 54 ( Suppl.1 ) S - 225 2011年4月

[Chemerin, RBP4 and vaspin]. 査読

Wada J, Teshigawara S, Nakatsuka A

Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 1 231 - 236 2011年1月

メタボリック症候群・慢性腎臓病の核内受容体をターゲットとした治療

中司敦子, 和田淳, 影近弘之, 肥田和之, 村上和敏, 神崎資子, 勅使川原早苗, 寺見隆宏, 井上謙太郎, 小川大輔, 四方賢一, 槇野博史

日本腎臓学会誌 52 ( 3 ) 321 - 321 2010年5月

メタボリック症候群・慢性腎臓病の核内受容体をターゲットとした治療

和田淳, 中司敦子, 影近弘之, 肥田和之, 村上和敏, 神崎資子, 勅使川原早苗, 寺見隆宏, 井上謙太郎, 小川大輔, 四方賢一, 槇野博史

糖尿病 53 ( Suppl.1 ) S - 251 2010年4月

RXRアンタゴニストによる細胞周期異常制御とメタボリック症候群

中司敦子, 和田淳, 村上和敏, 神崎資子, 勅使川原早苗, 井上謙太郎, 寺見隆宏, 黒瀬祐子, 四方賢一, 影近弘之, 槇野博史

糖尿病 52 ( Suppl.1 ) S - 246 2009年4月

ACAMの脂肪分化とメタボリックシンドロームにおける意義

村上和敏, 和田淳, 中司敦子, 勅使川原早苗, 神崎資子, 吉川理津子, 寺見隆宏, 井上謙太郎, 黒瀬祐子, 四方賢一, 槇野博史

糖尿病 52 ( Suppl.1 ) S - 162 2009年4月

ヒト血中Vaspin濃度の検討とメタボリックシンドロームにおける意義

勅使川原早苗, 和田淳, 中司敦子, 村上和敏, 神崎資子, 肥田和之, 伊勢田泉, 利根淳仁, 松下裕一, 宮武伸行, 井上謙太郎, 寺見隆宏, 黒瀬裕子, 四方賢一, 槇野博史

糖尿病 52 ( Suppl.1 ) S - 245 2009年4月

Collectrin Is Involved in the Development of Salt-Sensitive Hypertension by Facilitating the Membrane Trafficking of Apical Membrane Proteins via Interaction With Soluble N-Ethylmaleiamide-Sensitive Factor Attachment Protein Receptor Complex 査読

Akihiro Yasuhara, Jun Wada, Sandra M. Malakauskas, Yanling Zhang, Jun Eguchi, Atsuko Nakatsuka, Kazutoshi Murakami, Motoko Kanzaki, Sanae Teshigawara, Kazuya Yamagata, Thu H. Le, Hirofumi Makino

CIRCULATION 118 ( 21 ) 2146 - 2155 2008年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS

Background-Collectrin, a homologue of angiotensin converting enzyme 2, is expressed in pancreatic beta cells and renal proximal tubular and collecting duct cells under the control of hepatocyte nuclear factors-1 alpha and-1 beta. Because collectrin interacts with the soluble N-ethylmaleiamide-sensitive factor attachment protein receptor (SNARE) complexes, we investigated whether collectrin is involved in sodium handling in hypertension by vesicle trafficking of apical membrane proteins.
Methods and Results-Collectrin physically interacts with the SNARE complex: snapin, synaptosomal-associated protein 23 kDa, syntaxin-4, and vesicle-associated membrane protein-2 in mIMCD-3 cells. siRNA knockdown of collectrin resulted in a reduction in membrane-associated aquaporin-2, alpha-epithelial Na(+) channel, and H(+)-ATPase. Collectrin and SNARE proteins were abundantly expressed in collecting ducts of Wistar-Kyoto rats. Wistar-Kyoto rats and spontaneously hypertensive rats 7 weeks of age were subjected to normal-salt (1% NaCl) and high-salt (8% NaCl) chow for 10 weeks. High-salt chow prominently elevated blood pressure, oral intake, and urinary excretion of NaCl and water in both groups. Although urinary excretion of aldosterone was significantly suppressed in both groups, collectrin expression was upregulated and associated with the maintenance of aquaporin-2, alpha-epithelial Na(+) channel, and H(+)-ATPase in membrane fractions. Collectrin promoter activities and mRNA and protein expressions were upregulated and ubiquitinated collectrin was reduced by high NaCl (175 to 225 mmol/L) and not altered by 1 mu mol/L aldosterone in mIMCD-3 cells.
Conclusions-Upregulation of collectrin by high NaCl independent of aldosterone functionally links to the trafficking of apical membrane proteins via the SNARE complex, and collectrin may be responsible for the sodium retention in salt-sensitive hypertension. (Circulation. 2008; 118: 2146-2155.)

DOI： 10.1161/CIRCULATIONAHA.108.787259

ヒト血中Vaspin濃度の検討とメタボリックシンドロームにおける意義

勅使川原早苗, 和田淳, 中司敦子, 村上和敏, 神崎資子, 寺見隆宏, 井上謙太郎, 肥田和之, 伊勢田泉, 利根淳仁, 松下裕一, 宮武伸行, 四方賢一, 槇野博史

肥満研究 14 ( Suppl. ) 196 - 196 2008年9月

ACAMの脂肪分化とメタボリックシンドロームにおける意義

村上和敏, 和田淳, 中司敦子, 勅使川原早苗, 神崎資子, 寺見隆宏, 井上謙太郎, 四方賢一, 槇野博史

肥満研究 14 ( Suppl. ) 176 - 176 2008年9月

Adipocyte adhesion molecule (ACAM) inhibits adipocyte hypertrophy in obesity

Kazutoshi Murakami, Jun Wada, Atsuko Nakatsuka, Motoko Kanzaki, Sanae Teshigawara, Takahiro Terami, Kentaro Inoue, Hirofumi Makino

DIABETES 57 A110 - A111 2008年6月

Vaspin (visceral adipose tissue-derived serpin), improves insulin sensitivity in metabolic syndrome

Atsuko Nakatsuka, Jun Wada, Kazutoshi Murakami, Sanae Teshigawara, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Hirofumi Makino

DIABETES 57 A396 - A396 2008年6月

Galectin-9 inhibits the development of type 1 diabetes in female NOD mice

Motoko Kanzaki, Jun Wada, Atsuko Nakatsuka, Kazutoshi Murakami, Sanae Teshigawara, Takahiro Terami, Kentaro Inoue, Hirofumi Makino

DIABETES 57 A78 - A78 2008年6月

Serum vaspin levels correlate with the accumulation of visceral adipose tissues in type 2 diabetes patients

Sanae Teshigawara, Jun Wada, John Mcdonald, Jehangir Mistry, Atsuko Nakatsuka, Kazutoshi Murakami, Motoko Kanzaki, Takahiro Terami, Kentaro Inoue, Hirofumi Makino

DIABETES 57 A394 - A395 2008年6月

Procollagen C-proteinase enhancer-1 (POPE-1) interacts with beta 2-microglobulin (beta 2-m) and may help initiate beta 2-m amyloid fibril formation in connective tissues 査読

Hisanori Morimoto, Jun Wada, Bernard Font, Joni D. Mott, David J. S. Hulmes, Tadakazu Ookoshi, Hironobu Naiki, Akihiro Yasuhara, Atsuko Nakatsuka, Kousuke Fukuoka, Yuji Takatori, Haruo Ichikawa, Shigeru Akagi, Kazushi Nakao, Hirofumi Makino

MATRIX BIOLOGY 27 ( 3 ) 211 - 219 2008年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE BV

Dialysis related amyloidosis (DRA) is a progressive and serious complication in patients under long-term hemodialysis and mainly leads to osteo-articular diseases. Although beta 2-microglobulin (beta 2-m) is the major structural component of beta 2-m amyloid fibrils, the initiation of amyloid formation is not clearly understood. Here, we have identified procollagen C-proteinase enhance-1 (POPE-1) as a new interacting protein with beta 2-m by screening a human synovium cDNA library. The interaction of beta 2-m with full-length POPE-1 was confirmed by immunoprecipitation, solid-phase binding and pull-down assays. By yeast two-hybrid analysis and pull-down assay, beta 2-m appeared to interact with POPE-1 via the NTR (netrin-like) domain and not via the CUB (C1r/C1s, Uegf and BMP-1) domain region. In synovial tissues derived from hemodialysis patients with DRA, beta 2-m co-localized and formed a complex with POPE-1. beta 2-m did not alter the basal activity of bone morphogenetic protein-1/procollagen C-proteinase (BMP-1/PCP) nor BMP-1/PCP activity enhanced by PCPE-1. PCPE-1 did not stimulate beta 2-m amyloid fibril formation from monomeric beta 2-m in vitro under acidic and neutral conditions as revealed by thioflavin T fluorescence spectroscopy and electron microscopy. Since PCPE-1 is abundantly expressed in connective tissues rich in type I collagen, it may be involved in the initial accumulation of beta 2-m in selected tissues such as tendon, synovium and bone. Furthermore, since such preferential deposition of beta 2-m may be linked to subsequent beta 2-m amyloid fibril formation, the disruption of the interaction between beta 2-m and POPE-1 may prevent beta 2-m amyloid fibril formation and therefore POPE-1 could be a new target for the treatment of DRA. (C) 2007 Elsevier B.V./International Society of Matrix Biology. All rights reserved.

DOI： 10.1016/j.matbio.2007.11.005

ヒト血中Vaspin濃度の検討とメタボリックシンドロームにおける意義

勅使川原早苗, 和田淳, 中司敦子, 村上和敏, 肥田和之, 伊勢田泉, 利根淳仁, 松下裕一, 宮武伸行, 井上謙太郎, 寺見隆宏, 四方賢一, 槇野博史

糖尿病 51 ( Suppl.1 ) S - 308 2008年4月

Galectin-9による1型糖尿病発症抑制の検討

神崎資子, 和田淳, 吉川理津子, 中司敦子, 村上和敏, 安原章浩, 勅使川原早苗, 井上謙太郎, 寺見隆宏, 四方賢一, 槇野博史

糖尿病 51 ( Suppl.1 ) S - 211 2008年4月

ACAMの脂肪分化とメタボリックシンドロームにおける意義

村上和敏, 和田淳, 中司敦子, 神崎資子, 安原章浩, 吉川理津子, 勅使川原早苗, 井上謙太郎, 寺見隆宏, 四方賢一, 槇野博史

糖尿病 51 ( Suppl.1 ) S - 306 2008年4月

Vaspinのメタボリックシンドロームにおける意義

中司敦子, 和田淳, 村上和敏, 神崎資子, 安原章浩, 吉川理津子, 勅使川原早苗, 井上謙太郎, 寺見隆宏, 四方賢一, 槇野博史

糖尿病 51 ( Suppl.1 ) S - 307 2008年4月

Adipocyte adhesion molecule (ACAM) inhibits adipocyte hypertrophy in obesity

K. Murakami, J. Wada, A. Nakatsuka, S. Teshigawara, R. Yoshikawa, M. Kanzaki, A. Yasuhara, K. Shikata, H. Makino

DIABETOLOGIA 50 S57 - S57 2007年9月

Vaspin improves insulin sensitivity in obesity

A. Nakatsuka, J. Wada, K. Murakami, S. Teshigawara, R. Yoshikawa, M. Kanzaki, A. Yasuhara, K. Shikata, H. Makino

DIABETOLOGIA 50 S56 - S56 2007年9月

脂肪細胞分化 ACAMトランスジェニックマウスとメタボリック症候群

村上和敏, 和田淳, 中司敦子, 神崎資子, 勅使川原早苗, 四方賢一, 槇野博史

肥満研究 13 ( Suppl. ) 157 - 157 2007年9月

Vaspinとメタボリック症候群

中司敦子, 和田淳, 村上和敏, 神崎資子, 勅使川原早苗, 四方賢一, 槇野博史

肥満研究 13 ( Suppl. ) 193 - 193 2007年9月

Vaspin(visceral adipose tissue-derived serpin)とインスリン抵抗性

中司敦子, 和田淳, 村上和敏, 勅使川原早苗, 吉川理津子, 神崎資子, 四方賢一, 槇野博史

糖尿病 50 ( Suppl.1 ) S - 166 2007年4月

Adipocyte adhesion molecule(ACAM)トランスジェニックマウスとメタボリックシンドローム

村上和敏, 和田淳, 中司敦子, 勅使川原早苗, 吉川理津子, 神崎資子, 安原章浩, 四方賢一, 槇野博史

糖尿病 50 ( Suppl.1 ) S - 163 2007年4月

Hemophagocytic syndrome associated with fatal veno-occlusive disease in the liver 査読

Atsuko Nakatsuka, Jun Wada, Ryo Nagase, Masaya Takeda, Tadashi Yoshino, Hirofumi Makino

INTERNAL MEDICINE 46 ( 8 ) 495 - 499 2007年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

A 47-year-old man presented with hemophagocytic syndrome (HPS) without any obvious underlying diseases. On computed tomography, his liver was occupied by multiple ill-defined low intensity lesions. Liver biopsy revealed diffuse infiltration of numerous histiocytes without cytologic atypism and prominent fibrotic changes. These histiocyes showed S100(+), CD68(+), CD1a(-), and lysozyme(+) and Langerhans cell granules were not observed by electron microscopic examination. He failed to respond to immunosuppressive and chemotherapeutic treatments and progressed to severe liver failure. At autopsy, his liver exhibited veno-occulusive disease (VOD). Since VOD is regarded as a rare complication of HPS, the presence of VOD associated with HPS may be easily overlooked.

DOI： 10.2169/internalmedicine.46.6294

[Molecular biology of regulation in renal functions; biosynthesis, metabolism, and action of insulin and glucagon]. 査読

Nakatsuka A, Wada J, Makino H

Nihon rinsho. Japanese journal of clinical medicine 64 Suppl 2 222 - 226 2006年2月

Visceral adipose tissue-derived serine protease inhibitor: A unique insulin-sensitizing adipocytokine in obesity 査読

K Hida, J Wada, J Eguchi, H Zhang, M Baba, A Seida, L Hashimoto, T Okada, A Yasuhara, A Nakatsuka, K Shikata, S Hourai, J Futami, E Watanabe, Y Matsuki, R Hiramatsu, S Akagi, H Makino, YS Kanwar

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 102 ( 30 ) 10610 - 10615 2005年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：NATL ACAD SCIENCES

There is a rapid global rise in obesity, and the link between obesity and diabetes remains somewhat obscure. We identified an adipocytokine, designated as visceral adipose tissue-derived serpin (vaspin), which is a member of serine protease inhibitor family. Vaspin cDNA was isolated by from visceral white adipose tissues (WATs) of Otsuka Long-Evans Tokushima fatty (OLETIF) rat, an animal model of abdominal obesity with type 2 diabetes. Rat, mouse, and human vaspins are made up of 392,394, and 395 amino acids, respectively; exhibit approximate to 40% homology with alpha(1)-antitrypsin; and are related to serine protease inhibitor family. Vaspin was barely detectable in rats at 6 wk and was highly expressed in adipocytes of visceral WATs at 30 wk, the age when obesity, body weight, and insulin levels peak in OLETF rats. The tissue expression of vaspin and its serum levels decrease with worsening of diabetes and body weight loss at 50 wk. The expression and serum levels were normalized with the treatment of insulin or insulin-sensitizing agent, pioglitazone, in OLETF rats. Administration of vaspin to obese CRL:CD-1 (ICR) (ICR) mice fed with high-fat high-sucrose chow improved glucose tolerance and insulin sensitivity reflected by normalized serum glucose levels. It also led to the reversal of altered expression of genes relevant to insulin resistance, e.g., leptin, resistin, TNF alpha, glucose transporter-4, and adiponectin. In DNA chip analyses, vaspin treatment resulted in the reversal of expression in approximate to 50% of the high-fat high-sucrose-induced genes in WATs. These findings indicate that vaspin exerts an insulin-sensitizing effect targeted toward WATs in states of obesity.

DOI： 10.1073/pnas.0504703102

A case of monoclonal immunoglobulin light- and heavy-chain deposition disease exhibiting atypical deposition with fibrillary structures, successfully treated with chemotherapy. 査読

Nakatsuka A, Maeshima Y, Sarai A, Yanai H, Sugiyama H, Yamasaki Y, Makino H

Clin Nephrol 64 221 - 227 2005年

VASPIN(visceral adipose tissue specific SERPIN)とインスリン抵抗性

肥田和之, 和田淳, 江口潤, 松岡孝至, 橋本泉, 安原章浩, 中司敦子, 清田綾, 岡田達夫, 馬場雅子, 四方賢一, 槇野博史

糖尿病 47 ( Suppl.1 ) S252 - S252 2004年4月

糖尿病性腎症に対するPioglitazoneの作用メカニズムの検討

岡田達夫, 和田淳, 肥田和之, 江口潤, 橋本泉, 馬場雅子, 松岡孝至, 安原章浩, 清田綾, 中司敦子, 四方賢一, 槇野博史

糖尿病 47 ( Suppl.1 ) S195 - S195 2004年4月

白色脂肪特異的新規膜蛋白(OL-16)の機能解析

江口潤, 和田淳, 肥田和之, 松岡孝至, 馬場雅子, 中司敦子, 橋本泉, 清田綾, 安原章浩, 岡田達夫, 四方賢一, 槇野博史

肥満研究 9 ( Suppl. ) 76 - 76 2003年10月

A case of focal segmental glomerulosclerosis (FSGS) complicated with chronic hepatitis B and treated with steroid and LDL apheresis 査読

Akinobu Takaki, Atsuko Nakatsuka, Chikage Satou, Yasuyoshi Iwata, Hiroshi Ikeda, Masaki Fukushima

Japanese Journal of Nephrology 44 ( 8 ) 806 - 812 2002年

記述言語：日本語掲載種別：研究論文（学術雑誌）

A 52-year-old man was admitted to our hospital because of nephrotic syndrome. He had been monitored at our outpatient clinic for chronic hepatitis B, and had experienced histologically proven minimal change nephrotic syndrome at the ages of 40 and 51 years. Because of HBsAg positivity in his serum, steroid therapy was withheld in his earlier episodes and he recovered from nephrotic syndrome spontaneously. However, in the most recent episode the nephrotic syndrome was found difficult to control and the findings of renal biopsy showed FSGS, which is not expected in HBV-associated nephropathy. Finally, prednisolone was administered at the dose of 40 mg/day for four weeks, after which the dose was tapered. LDL apheresis was also administered three times because of the patient's incomplete response to prednisolone. His proteinuria was reduced from&gt
10 g/day to&lt
1 g/day, but the ALT levels and HBsAg titer increased. With stronger neominophagen C induction and very careful tapering of glucocorticoid, ALT levels and the HBsAg titer decreased. During the two-year period since the induction of glucocorticoid therapy, urinary protein excretion has been maintained at less than 1 g/gcr, and ALT levels and HBsAg titer have not increased. We conclude that attention must be paid to dose modification of steroid therapy and strategies without immunosuppressive agents such as LDL apheresis should be considered in the case of treatment of nephrotic syndrome with HB virus.

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