Carboxylesterase 1d (Ces1d) does not contribute to cholesteryl ester hydrolysis in the liver

• Published in: Journal of lipid research Vol. 62; p. 100093
• Main Authors: Lian, Jihong, van der Veen, Jelske N., Watts, Russell, Jacobs, René L., Lehner, Richard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021; American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: Animals; carboxylesterase; Carboxylesterase - deficiency; Carboxylesterase - metabolism; cardiovascular disease; Cells, Cultured; Cholesterol Esters - metabolism; cholesterol metabolism; cholesteryl ester hydrolase; HDL; Hydrolysis; lipase activity; liver; Liver - metabolism; Mice; Mice, Knockout; Mice, Transgenic; reverse cholesterol transport; VLDL; Western-type diet; RCT; SR-BI; WTD; WAT; CYP7A1; HDL; lipase activity; VLDL; SHP; Ces1d; cholesteryl ester hydrolase; HSL; cardiovascular disease; reverse cholesterol transport; liver; cholesterol metabolism; carboxylesterase; TC; LKO; AADAC; Lox; Western-type diet; LD; 4-MU; FC
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1016/j.jlr.2021.100093

The liver is the central organ regulating cholesterol synthesis, storage, transport, and elimination. Mouse carboxylesterase 1d (Ces1d) and its human ortholog CES1 have been described to possess lipase activity and play roles in hepatic triacylglycerol metabolism and VLDL assembly. It has been proposed that Ces1d/CES1 might also catalyze cholesteryl ester (CE) hydrolysis in the liver and thus be responsible for the hydrolysis of HDL-derived CE; this could contribute to the final step in the reverse cholesterol transport (RCT) pathway, wherein 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. In this study, 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 a high-cholesterol diet challenge. We found that liver-specific Ces1d-deficient mice did not show any difference in the flux of in vivo HDL-to-feces RCT nor did it cause additional liver CE accumulation after high-fat, high-cholesterol Western-type diet feeding. These findings challenge the importance of Ces1d as a major hepatic CE hydrolase.