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12 alpha-Hydroxylated bile acid induces hepatic steatosis with dysbiosis in rats

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Title: 12 alpha-Hydroxylated bile acid induces hepatic steatosis with dysbiosis in rats
Authors: Lee, Ja-Young Browse this author
Shimizu, Hidehisa Browse this author
Hagio, Masahito Browse this author
Fukiya, Satoru Browse this author
Watanabe, Masamichi Browse this author
Tanaka, Yasutake Browse this author
Joe, Ga-Hyun Browse this author
Iwaya, Hitoshi Browse this author
Yoshitsugu, Reika Browse this author
Kikuchi, Keidai Browse this author
Tsuji, Misaki Browse this author
Baba, Nanako Browse this author
Nose, Takuma Browse this author
Tada, Koji Browse this author
Hanai, Taketo Browse this author
Hori, Shota Browse this author
Takeuchi, Akari Browse this author
Furukawa, Yumiko Browse this author
Shirouchi, Bungo Browse this author
Sato, Masao Browse this author
Ooka, Tadasuke Browse this author
Ogura, Yoshitoshi Browse this author
Hayashi, Tetsuya Browse this author
Yokota, Atsushi Browse this author
Ishizuka, Satoshi Browse this author →KAKEN DB
Keywords: Cholic acid
Deoxycholic acid
4 beta-Hydroxycholesterol
Non-alcoholic fatty liver disease
Simple hepatic steatosis
Issue Date: Dec-2020
Publisher: Elsevier
Journal Title: Biochimica et Biophysica Acta (BBA) Molecular and Cell Biology of Lipids
Volume: 1865
Issue: 12
Start Page: 158811
Publisher DOI: 10.1016/j.bbalip.2020.158811
Abstract: There is an increasing need to explore the mechanism of the progression of non-alcoholic fatty liver disease. Steroid metabolism is closely linked to hepatic steatosis and steroids are excreted as bile acids (BAs). Here, we demonstrated that feeding WKAH/HkmSlc inbred rats a diet supplemented with cholic acid (CA) at 0.5 g/kg for 13 weeks induced simple steatosis without obesity. Liver triglyceride and cholesterol levels were increased accompanied by mild elevation of aminotransferase activities. There were no signs of inflammation, insulin resistance, oxidative stress, or fibrosis. CA supplementation increased levels of CA and taurocholic acid (TCA) in enterohepatic circulation and deoxycholic acid (DCA) levels in cecum with an increased ratio of 12 alpha-hydroxylated BAs to non-12 alpha-hydroxylated BAs. Analyses of hepatic gene expression revealed no apparent feedback control of BA and cholesterol biosynthesis. CA feeding induced dysbiosis in cecal microbiota with enrichment of DCA producers, which underlines the increased cecal DCA levels. The mechanism of steatosis was increased expression of Srebp1 (positive regulator of liver lipogenesis) through activation of the liver X receptor by increased oxysterols in the CA-fed rats, especially 4 beta-hydroxycholesterol (4 beta OH) formed by upregulated expression of hepatic Cyp3a2, responsible for 4 beta OH formation. Multiple regression analyses identified portal TCA and cecal DCA as positive predictors for liver 4 beta OH levels. The possible mechanisms linking these predictors and upregulated expression of Cyp3a2 are discussed. Overall, our observations highlight the role of 12 alpha-hydroxylated BAs in triggering liver lipogenesis and allow us to explore the mechanisms of hepatic steatosis onset, focusing on cholesterol and BA metabolism.
Type: article
Appears in Collections:農学院・農学研究院 (Graduate School of Agriculture / Faculty of Agriculture) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

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