Lian_2021_J.Lipid.Res__100093

Mouse carboxylesterase 1d (Ces1d) and its human ortholog CES1 have been described to possess lipase activity and play a role in hepatic triacylglycerol (TG) metabolism and very-low density lipoprotein (VLDL) assembly. Liver is a central organ regulating cholesterol synthesis, storage, transport, and elimination. It has been proposed that Ces1d/CES1 might also catalyze cholesteryl ester (CE) hydrolysis in the liver and be responsible for the hydrolysis of high-density lipoprotein (HDL)-derived CE, thus contributing to the final step in the reverse cholesterol transport (RCT) pathway, where cholesterol is secreted from the liver into bile and feces, either directly or after conversion to water-soluble bile salts. However, the proposed function of Ces1d/CES1 as a CE hydrolase is controversial. We interrogated the role hepatic Ces1d plays in cholesterol homeostasis using liver-specific Ces1d deficient mice. We rationalized that if Ces1d is a major hepatic CE hydrolase, its absence would 1) reduce in vivo RCT flux, and 2) provoke liver CE accumulation after high cholesterol diet challenge. In this study, liver-specific Ces1d KO mice did not show any difference in the flux of in vivo HDL-to-feces RCT and did not cause additional liver CE accumulation after high-fat, high cholesterol Western-type diet (WTD) feeding, thereby challenging the importance of Ces1d as a major hepatic CE hydrolase.