研究者詳細 - 佐藤　生弥

論文 - 佐藤　生弥

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Distribution and Incorporation of Extracellular Vesicles into Chondrocytes and Synoviocytes

Takashi Ohtsuki, Ikumi Sato, Ren Takashita, Shintaro Kodama, Kentaro Ikemura, Gabriel Opoku, Shogo Watanabe, Takayuki Furumatsu, Hiroshi Yamada, Mitsuru Ando, Kazunari Akiyoshi, Keiichiro Nishida, Satoshi Hirohata

International Journal of Molecular Sciences 2024年11月

Uric Acid Elevation by Fructose Overload Exacerbates Nash and Atherosclerosis via Oxidative Stress 査読

Moe Fujii, Mai Kakimoto, Ikumi Sato, Koki Honma, Sora Kirihara, Hinako Nakayama, Taketo Fukuoka, Satoshi Hirohata, Kazuya Kitamori, Shang Ran, Shusei Yamamoto, Shogo Watanabe

Current Nutrition & Food Science 20 ( 2 ) 250 - 261 2024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：Bentham Science Publishers Ltd.

Background:

Nonalcoholic steatohepatitis (NASH) is well associated with an increasedrisk of cardiovascular disease (CVD), regardless of risk factors for metabolic syndrome. However,intermediary factors between NASH and CVD remain unknown. In recent years, hyperuricemia hasbeen associated not only with gout but also with several other organ diseases, such as hypertension,chronic renal failure, and metabolic syndrome. In addition, hyperuricemia was shown to frequentlyoccur in patients with NASH and could be a risk factor for CVD. Furthermore, serum uric acid(UA) levels have been linked with fructose intake.

Objectives:

We hypothesized that fructose loading elevates UA levels and exacerbates NASH andatherosclerosis via oxidative stress.

Methods:

Stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr), between 14 to 24 weeksof age, were divided into two groups and fed a high-fat and high-cholesterol (HFC) diet. In additionto the HFC diet, the fructose group was subjected to 10% fructose loading. The oral glucose tolerancetest (OGTT) and insulin tolerance test (ITT) were performed at 25-week-old, followed byblood sampling, animal sacrifice, endothelial function test, blood biochemistry, histopathologicalstaining, xanthine oxidase activity test, and genetic analysis performed at 26-week-old.

Results:

Fructose loading increased UA and oxidative stress levels. In addition, fructose loadinginduced insulin resistance. The fructose group exhibited aggravated hepatic fibrosis and lipid deposition,as well as enhanced lipid accumulation in the mesenteric arteries.

Conclusion:

In the SHRSP5/Dmcr rat model, elevated UA levels were a risk factor for the exacerbationof NASH and atherosclerosis via oxidative stress.

DOI： 10.2174/1573401319666230508150159

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その他リンク： https://www.eurekaselect.com/216665/article

Therapeutic effect of ouabagenin, a novel liver X receptor agonist, on atherosclerosis in nonalcoholic steatohepatitis in SHRSP5/Dmcr rat model 査読

Shusei Yamamoto, Ikumi Sato, Moe Fujii, Mai Kakimoto, Koki Honma, Sora Kirihara, Hinako Nakayama, Taketo Fukuoka, Satoru Tamura, Minoru Ueda, Satoshi Hirohata, Shogo Watanabe

Canadian Journal of Physiology and Pharmacology 101 ( 9 ) 455 - 465 2023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：Canadian Science Publishing

The liver X receptor (LXR) can enhance cholesterol transporters, which could remove excess cholesterol from foam cells in atheromas. LXR has two subtypes: LXRα, which aggravates hepatic lipid accumulation, and LXRβ, which does not. In 2018, ouabagenin (OBG) was reported as a potential LXRβ-specific agonist. We aimed to examine whether OBG specifically affects LXRβ in nonalcoholic steatohepatitis (NASH); it did not aggravate hepatic steatosis and can suppress the development of atherosclerosis. SHRSP5/Dmcr rats fed a high-fat and high-cholesterol diet were divided into four groups as follows: (I) L-NAME group, (II) L-NAME/OBG group, (III) OBG (−) group, and (IV) OBG (+) group. All groups’ rats were intraperitoneally administered L-NAME. The L-NAME/OBG group’s rats were intraperitoneally administered OBG and L-NAME simultaneously. After L-NAME administration, the OBG (+) group’s rats were administered OBG, while the OBG (−) group’s rats were not. Although all rats developed NASH, OBG did not exacerbate steatosis (L-NAME/OBG and OBG (+) groups). In addition, endothelial cells were protected in the L-NAME/OBG group and foam cells in the atheroma were reduced in the OBG (+) group. OBG is an LXRβ-specific agonist and has a potential therapeutic effect on atherosclerosis without developing lipid accumulation in the liver.

DOI： 10.1139/cjpp-2022-0532

PubMed

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その他リンク： https://cdnsciencepub.com/doi/pdf/10.1139/cjpp-2022-0532

SHRSP5/Dmcr rats fed a high-fat and high-cholesterol diet develop disease-induced sarcopenia as nonalcoholic steatohepatitis progresses 査読

Shusei Yamamoto, Koki Honma, Moe Fujii, Mai Kakimoto, Sora Kirihara, Hinako Nakayama, Kazuya Kitamori, Ikumi Sato, Satoshi Hirohata, Shogo Watanabe

Annals of Anatomy - Anatomischer Anzeiger 249 152104 - 152104 2023年8月

Selective autophagy associated with iron overload aggravates non-alcoholic steatohepatitis via ferroptosis 査読

Koki Honma, Sora Kirihara, Hinako Nakayama, Taketo Fukuoka, Toshiaki Ohara, Kazuya Kitamori, Ikumi Sato, Satoshi Hirohata, Moe Fujii, Shusei Yamamoto, Shang Ran, Shogo Watanabe

Experimental Biology and Medicine 248 ( 13 ) 1112 - 1123 2023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：Frontiers Media SA

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that causes cirrhosis and hepatocellular carcinoma. Iron is an essential trace element in the body; however, excess iron can cause tissue damage and dysfunction. Iron overload is often observed in patients with NASH, and the amount of iron accumulated in the liver positively correlates with the histological severity of NASH. Ferroptosis, a novel form of iron-dependent cell death, is caused by the accumulation of lipid peroxidation and oxidative stress and is related to NASH. In addition, ferroptosis is closely related to autophagy, an intracellular self-degradation process. Although autophagy has many beneficial effects, it may also be harmful to the organism, for example, inducing ferroptosis. It is unclear whether iron overload aggravates NASH via autophagy. The aim of this research is to determine the mechanism by which iron overload induces ferroptosis via autophagy and aggravates NASH. Stroke-prone spontaneously hypertensive rats (SHRSP5/Dmcr) were divided into two groups and fed a high-fat and high-cholesterol (HFC) diet for eight weeks. Iron dextran was administered to the Fe group in addition to the HFC diet. Blood analysis, histological staining, calcineurin activity assay, quantitative reverse transcription polymerase chain reaction (RT-PCR), immunofluorescence staining, and electron microscopy were performed. The results showed that iron overload promoted autophagy via nuclear translocation of transcription factor EB (TFEB) and induced ferritinophagy, which is the autophagic degradation of ferritin. In addition, the HFC diet induced lipophagy, the autophagic degradation of lipid droplets. The Fe group also exhibited promoted ferroptosis and aggravated hepatic inflammation and fibrosis. In conclusion, iron overload accelerates ferritinophagy and lipophagy, aggravating NASH pathology via ferroptosis. These findings indicate the therapeutic potential of inhibiting autophagy and ferroptosis for treating NASH.

DOI： 10.1177/15353702231191197

PubMed

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その他リンク： http://journals.sagepub.com/doi/full-xml/10.1177/15353702231191197

Antioxidant action of xanthine oxidase inhibitor febuxostat protects the liver and blood vasculature in SHRSP5/Dmcr rats 査読

Mai Kakimoto, Moe Fujii, Ikumi Sato, Koki Honma, Hinako Nakayama, Sora Kirihara, Taketo Fukuoka, Shang Ran, Satoshi Hirohata, Kazuya Kitamori, Shusei Yamamoto, Shogo Watanabe

Journal of Applied Biomedicine 21 ( 2 ) 80 - 90 2023年6月

Increased Glycine-conjugated and Unconjugated Bile Acid Levels Associated with Aggravation of Nonalcoholic Steatohepatitis and Cardiovascular Disease in SHRSP5/Dmcr Rat. 査読

Shusei Yamamoto, Ikumi Sato, Moe Fujii, Mai Kakimoto, Koki Honma, Natsumi Akiyama, Miku Sakai, Natsuki Fukuhama, Shota Kumazaki, Satoshi Hirohata, Kazuya Kitamori, Yukio Yamori, Shogo Watanabe

Acta medica Okayama 77 ( 1 ) 29 - 36 2023年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

The SHRSP5/Dmcr is a useful animal model for the development of nonalcoholic steatohepatitis (NASH) pathology when fed a high-fat, high-cholesterol diet, and further drug interventions can lead to concomitant cardiovascular disease. While SHRSP5/Dmcr rats have been used for basic research related to NASH, details of their bile acid metabolism in this condition are unknown. In this study, we aimed to clarify the changes in the serum bile acid (BA) fractions associated with NASH and found that glycine-conjugated and unconjugated bile acid increased with worsening NASH and cardiovascular disease while taurine-conjugated BA relatively decreased.

DOI： 10.18926/AMO/64358

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Suppression of nitric oxide synthase aggravates non-alcoholic steatohepatitis and atherosclerosis in SHRSP5/Dmcr rat via acceleration of abnormal lipid metabolism 査読

Ikumi Sato, Shusei Yamamoto, Mai Kakimoto, Moe Fujii, Koki Honma, Shota Kumazaki, Mami Matsui, Hinako Nakayama, Sora Kirihara, Shang Ran, Shinichi Usui, Ryoko Shinohata, Kazuya Kitamori, Satoshi Hirohata, Shogo Watanabe

Pharmacological Reports 74 ( 4 ) 669 - 683 2022年7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：Springer Science and Business Media LLC

DOI： 10.1007/s43440-022-00380-1

PubMed

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その他リンク： https://link.springer.com/article/10.1007/s43440-022-00380-1/fulltext.html

Basic characteristics between mechanomyogram and muscle force during twitch and tetanic contractions in rat skeletal muscles 査読

Ikumi Sato, Shusei Yamamoto, Mai Kakimoto, Moe Fujii, Koki Honma, Shota Kumazaki, Mami Matsui, Hinako Nakayama, Sora Kirihara, Shang Ran, Satoshi Hirohata, Shogo Watanabe

Journal of Electromyography and Kinesiology 62 102627 - 102627 2022年2月

Bile acids aggravate nonalcoholic steatohepatitis and cardiovascular disease in SHRSP5/Dmcr rat model 査読

Shusei Yamamoto, Ikumi Sato, Natsuki Fukuhama, Natsumi Akiyama, Miku Sakai, Shota Kumazaki, Shang Ran, Satoshi Hirohata, Kazuya Kitamori, Yukio Yamori, Shogo Watanabe

Experimental and Molecular Pathology 114 104437 - 104437 2020年6月

Bile Acid Metabolism is an Intermediary Factor between Non-Alcoholic Steatohepatitis and Ischemic Heart Disease in SHRSP5/Dmcr Rats 査読国際誌

Shota Kumazaki, Mayu Nakamura, Shun Sasaki, Rina Tagashira, Nozomi Maruyama, Ikumi Sato, Shusei Yamamoto, Shang Ran, Shinichi Usui, Ryoko Shinohata, Takashi Ohtsuki, Satoshi Hirohata, Kazuya Kitamori, Mari Mori, Yukio Yamori, Shogo Watanabe

Journal of Nutrition & Food Sciences 9 ( 4 ) 763 2019年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

The non-alcoholic steatohepatitis (NASH) increases the cardiovascular risk regardless of risk factors in metabolic syndrome. The stroke-prone (SP) spontaneously hypertensive rats (SHRSP5/Dmcr), fed a high-fat and -cholesterol (HFC) diet and administered Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME) presented NASH and cardiovascular disease. However, the intermediary factors between NASH and cardiovascular risk are still unknown. We investigated whether bile acids (BAs) play an intermediary role between NASH and cardiovascular disease in SHRSP5/Dmcr rats. SHRSP5/Dmcr rats divided into 2 groups were fed an SP (non-NASH group, n=7) or HFC diet (NASH group, n=10) for 8 weeks. L-NAME was administered intraperitoneally in the final 2 weeks. In the
NASH group, total BA levels were increased in both serum and liver; they aggravated the endothelial dysfunction in aorta, which is the first step to atherosclerosis, and activated the gene expression levels of cell adhesion molecules (vascular cell adhesion molecule-1, intercellular adhesion molecule-1) in coronary artery. In particular, the nuclear factor-kappa B (NFkB) was increased in the NASH group in the coronary endothelial cells activated by high BA levels. We demonstrated that liver BAs aggravated steatosis and fibrosis and serum BA accelerated arteriosclerosis and ischemic heart disease via the classical pathway of NFkB in the endothelial cells. BA metabolism disorder may
be an intermediary factor between NASH and cardiovascular risk in SHRSP5/Dmcr rats.

DOI： 10.35248/2155-9600.19.9.1000763

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Non‐alcoholic steatohepatitis aggravates nitric oxide synthase inhibition‐induced arteriosclerosis in <scp>SHRSP</scp>5/Dmcr rat model 査読

Shogo Watanabe, Shota Kumazaki, Shusei Yamamoto, Ikumi Sato, Kazuya Kitamori, Mari Mori, Yukio Yamori, Satoshi Hirohata

International Journal of Experimental Pathology 99 ( 6 ) 282 - 294 2018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

Summary

Non‐alcoholic steatohepatitis (NASH) is linked to increased cardiovascular risk, independent of the broad spectrum of metabolic syndrome risk factors. Stroke‐prone (SP) spontaneously hypertensive rats (SHRSP5/Dmcr) fed a high‐fat and high‐cholesterol (HFC) diet developed hepatic lesions similar to those in human NASH pathology. These rats simultaneously developed lipid deposits in the mesenteric arteries, cardiac fibrosis, endothelial dysfunction and left ventricle (LV) diastolic dysfunction. However, the intermediary factors between NASH and cardiovascular disease are still unknown. We investigated whether NASH aggravates nitric oxide (NO) synthase inhibition‐induced arteriosclerosis in SHRSP5/Dmcr rats. Wistar Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 and fed the stroke‐prone (SP) or HFC diets for 8 weeks. To induce NO synthase inhibition, N^ω‐nitro‐L‐arginine methyl ester hydrochloride (L‐NAME) mixed with drinking water was administered in the final 2 weeks. The NASH+L‐NAME group demonstrated the following characteristics related to arteriosclerosis and myocardial ischaemia: (a) LV systolic dysfunction with asynergy, (b) replacement fibrosis caused by the shedding of cardiomyocytes and (c) arterial lipid deposition and coronary occlusion secondary to endothelial dysfunction. These characteristics were not observed in the NASH or non‐NASH+L‐NAME groups. The SHRSP5/Dmcr rat model demonstrates that NASH significantly aggravates cardiovascular risk.

DOI： 10.1111/iep.12301

PubMed

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その他リンク： https://onlinelibrary.wiley.com/doi/pdf/10.1111/iep.12301

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