Jiesi Xu1, Yuanyuan Li1, Wei-Dong Chen1,2, Yang Xu1, Liya Yin1, Xuemei Ge1, Kavita Jadhav1, Luciano Adorini3, Yanqiao Zhang1. 1. Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA. 2. Key laboratory of receptor-mediated gene regulation and drug discovery, School of Medicine, Henan University, Kaifeng, China. 3. Intercept Pharmaceuticals, 18 Desbrosses Street, New York, NY 10013, USA.
Abstract
UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR-controlled lipid homeostasis. Overexpression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild-type and diabetic mice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1-dependent manner. CONCLUSION: Hepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR-controlled lipid homeostasis.
UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR-controlled lipid homeostasis. Overexpression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild-type and diabeticmice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1-dependent manner. CONCLUSION:Hepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR-controlled lipid homeostasis.
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