Transgenic expression of CYP7A1 in the liver prevents high fat diet‐induced obesity and insulin resistance in mice

Abstract

Bile acid‐activated FXR plays a key role in lipid, glucose, drug and energy metabolism. Cholesterol 7á‐hydroxylase (CYP7A1) catalyzes the rate‐limiting step in the conversion of cholesterol into bile acids in the liver. The mechanism of bile acid‐mediated regulation of glucose and lipid metabolism remains unclear. The objective of this study is to investigate the role of CYP7A1 in the prevention of fatty liver, obesity and diabetes. Transgenic mice carrying an ApoE3‐CYP7A1 coding sequence (Cyp7a1‐tg) were used to study high fat diet (HFD) induced obesity, fatty liver, and insulin resistance. Cyp7a1‐tg mice had a ~ 3‐fold higher bile acid pool size than wild type mice. When fed a HFD, Cyp7a1‐tg mice were resistant to weight gain, fatty liver and insulin resistance, and had decreased fat mass and hepatic triglycerides and cholesterol content than wild type mice. Cyp7a1‐tg mice showed increased hepatic VLDL secretion but maintained plasma triglyceride and cholesterol homeostasis. Indirect calorimetry revealed that HFD fed Cyp7a1‐tg mice had increased energy expenditure and higher respiratory quotient than wild type mice. This study suggests that maintaining bile acid homeostasis is important in regulating whole body lipid, glucose and energy homeostasis. Bile acids and derivative may be potential therapeutic agents for treating metabolic disorders such as fatty liver diseases, obesity and diabetes in humans.