New Key Publication: 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.

BY:

• Rumei Li
• Anna Palmiotti
• Hilde D. de Vries
• Milaine V. Hovingh
• Martijn Koehorst
• Niels L. Mulder
• Yue Zhang
• Kim Kats
• Vincent W. Bloks
• Jingyuan Fu
• Henkjan Verkade
• Jan Freark de Boer
• Folkert Kuipers

Read more: Journal of lipid research