| First Author | Li R | Year | 2021 |
| Journal | J Lipid Res | Volume | 62 |
| Pages | 100134 | PubMed ID | 34626589 |
| Mgi Jnum | J:322591 | Mgi Id | MGI:6828590 |
| Doi | 10.1016/j.jlr.2021.100134 | Citation | Li R, et al. (2021) Low production of 12alpha-hydroxylated bile acids prevents hepatic steatosis in Cyp2c70(-/-) mice by reducing fat absorption. J Lipid Res :100134 |
| abstractText | Bile acids (BAs) play important roles in lipid homeostasis and BA signaling pathways serve as therapeutic targets for non-alcoholic fatty liver disease (NAFLD). Recently, we generated Cyp2c70(-/-) mice with a human-like BA composition lacking mouse/rat-specific muricholic acids (MCAs) to accelerate translation from mice to humans. We employed this model to assess the consequences of a human-like BA pool on diet-induced obesity and NAFLD development. Male and female Cyp2c70(-/-) mice and wild-type (WT) littermates were challenged with a 12-week Western-type high-fat diet (WTD) supplemented with 0.25% cholesterol. Cyp2c70-deficiency induced a hydrophobic BA pool with high abundances of chenodeoxycholic acid, particularly in females, due to sex-dependent suppression of sterol 12alpha-hydroxylase (Cyp8b1). Plasma transaminases were elevated and hepatic fibrosis was present in Cyp2c70(-/-) mice, especially in females. Surprisingly, female Cyp2c70(-/-) mice were resistant to WTD-induced obesity and hepatic steatosis while male Cyp2c70(-/-) mice showed similar adiposity and moderately reduced steatosis compared to WT controls. Both intestinal cholesterol and fatty acid absorption were reduced in Cyp2c70(-/-) mice, the latter more strongly in females, despite unaffected biliary BA secretion rates. Intriguingly, the biliary ratio 12alpha-/non-12alpha-hydroxylated BAs significantly correlated with fatty acid absorption and hepatic triglyceride content as well as with specific changes in gut microbiome composition. The hydrophobic human-like BA pool in Cyp2c70(-/-) mice prevents WTD-induced obesity in female mice and NAFLD development in both genders, primarily due to impaired intestinal fat absorption. Our data point to a key role for 12alpha-hydroxylated BAs in control of intestinal fat absorption and modulation of gut microbiome composition. |
