12α-Hydroxylated bile acid induces hepatic steatosis with dysbiosis in rats
| Autor: | Nanako Baba, Masamichi Watanabe, Satoshi Ishizuka, Masao Sato, Hitoshi Iwaya, Yoshitoshi Ogura, Yasutake Tanaka, Koji Tada, Misaki Tsuji, Tadasuke Ooka, Reika Yoshitsugu, Yumiko Furukawa, Tetsuya Hayashi, Ja Young Lee, Keidai Kikuchi, Hidehisa Shimizu, Shota Hori, Masahito Hagio, Satoru Fukiya, Ga Hyun Joe, Taketo Hanai, Takuma Nose, Atsushi Yokota, Akari Takeuchi, Bungo Shirouchi |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Taurocholic Acid medicine.medical_specialty medicine.drug_class Hydroxylation Bile Acids and Salts 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Non-alcoholic Fatty Liver Disease Internal medicine medicine Cholic acid Animals Rats Wistar Liver X receptor Molecular Biology Enterohepatic circulation Bile acid Deoxycholic acid Fatty liver Cholic Acids Cell Biology medicine.disease Hydroxycholesterols Rats 030104 developmental biology Endocrinology chemistry Lipogenesis Dysbiosis 4 beta-Hydroxycholesterol 030211 gastroenterology & hepatology Steatosis Simple hepatic steatosis Deoxycholic Acid |
| Zdroj: | Biochimica et biophysica acta. Molecular and cell biology of lipids. 1865(12) |
| ISSN: | 1879-2618 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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