Abstract 435: Hepatic Carboxylesterase 1 is Essential for Maintaining Hepatic Triglyceride and Plasma Cholesterol Homeostasis and is Regulated by the Farnesoid X Receptor

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide, and is associated with increased risk of cardiovascular disease. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD and lipid disorders. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in lipid and carbohydrate metabolism. We found that the hepatic CES1 expression is affected by the status of glucose. Over-expression of hepatic CES1 lowered the levels of hepatic TG and plasma glucose in both wild-type and diabetic mice. Knockdown of hepatic CES1 increased both hepatic TG level and plasma cholesterol level. Such effects of CES1 likely resulted from its TG hydrolase activity, and subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Hepatic CES1 was also inducible by FXR and was indispensable for activated FXR to improve both hepatic and plasma lipid homeostasis. Thus, hepatic CES1 plays a critical role in regulating lipid and carbohydrate metabolism and in FXR-controlled lipid homeostasis.