Cytochrome P450 2E1 gene knockout or inhibition prevents obesity induced by high-fat diet via regulating energy expenditure

Abstract

Cytochrome P450 2E1 (CYP2E1), an important member of the CYP metabolic enzyme family in the liver, regulates the disposal of drugs and the biotransformation of endogenous substances. Although previous studies have found that CYP2E1 is related to energy metabolism, the role of CYP2E1 in energy homeostasis remains unclear. Herein this study shows that the deletion of Cyp2e1 gene in rats can prevent obesity, fatty liver and insulin resistance induced by high-fat diet. Mechanism studies uncover that Cyp2e1 deficiency not only increases the expression of thermogenic genes in brown adipose tissue (BAT) and subcutaneous adipose tissue (SAT), but also promotes fatty acid metabolism in the liver and BAT. In particular, Cyp2e1 deficiency elevates energy expenditure through an increase of liver-generated acylcarnitines, which promote BAT thermogenesis and increase β-oxidation. Interestingly, disulfiram as a CYP2E1 inhibitor can also prevent obesity induced by high-fat diet in normal rats. In general, this study explains the relationship between CYP2E1 and energy metabolism, and provides a new perspective for the prevention and treatment of obesity.