Dataset Information

Low production of 12α-hydroxylated bile acids prevents hepatic steatosis in Cyp2c70^-/- mice by reducing fat absorption.

ABSTRACT: 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 12α-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 12α-/non-12α-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 12α-hydroxylated BAs in control of intestinal fat absorption and modulation of gut microbiome composition.

SUBMITTER: Li R

PROVIDER: S-EPMC8596750 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundSignificantly elevated serum and hepatic bile acid (BA) concentrations have been known to occur in patients with liver fibrosis. However, the roles of different BA species in liver fibrogenesis are not fully understood.MethodsWe quantitatively measured blood BA concentrations in nonalcoholic steatohepatitis (NASH) patients with liver fibrosis and healthy controls. We characterized BA composition in three mouse models induced by carbon tetrachloride (CCl4), streptozotocin-high fat diet (STZ-HFD), and long term HFD, respectively. The molecular mechanisms underlying the fibrosis-promoting effects of BAs were investigated in cell line models, a 3D co-culture system, and a Tgr5 (HSC-specific) KO mouse model.FindingsWe found that a group of conjugated 12α-hydroxylated (12α-OH) BAs, such as taurodeoxycholate (TDCA) and glycodeoxycholate (GDCA), significantly increased in NASH patients and liver fibrosis mouse models. 12α-OH BAs significantly increased HSC proliferation and protein expression of fibrosis-related markers. Administration of TDCA and GDCA directly activated HSCs and promoted liver fibrogenesis in mouse models. Blockade of BA binding to TGR5 or inhibition of ERK1/2 and p38 MAPK signaling both significantly attenuated the BA-induced fibrogenesis. Liver fibrosis was attenuated in mice with Tgr5 depletion.InterpretationIncreased hepatic concentrations of conjugated 12α-OH BAs significantly contributed to liver fibrosis via TGR5 mediated p38MAPK and ERK1/2 signaling. Strategies to antagonize TGR5 or inhibit ERK1/2 and p38 MAPK signaling may effectively prevent or reverse liver fibrosis.FundingsThis study was supported by the National Institutes of Health/National Cancer Institute Grant 1U01CA188387-01A1, the National Key Research and Development Program of China (2017YFC0906800); the State Key Program of National Natural Science Foundation (81430062); the National Natural Science Foundation of China (81974073, 81774196), China Postdoctoral Science Foundation funded project, China (2016T90381), and E-institutes of Shanghai Municipal Education Commission, China (E03008).

Dataset Information

Low production of 12α-hydroxylated bile acids prevents hepatic steatosis in Cyp2c70^-/- mice by reducing fat absorption.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Low production of 12α-hydroxylated bile acids prevents hepatic steatosis in Cyp2c70-/- mice by reducing fat absorption.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Low production of 12α-hydroxylated bile acids prevents hepatic steatosis in Cyp2c70^-/- mice by reducing fat absorption.