Hepatocyte‐Specific Expression of Human Carboxylesterase 1 Attenuates Diet‐Induced Steatohepatitis and Hyperlipidemia in Mice

Abstract

Rodents have at least five carboxylesterase 1 (Ces1) genes, whereas there is only one CES1 gene in humans, raising the question as to whether human CES1 and mouse Ces1 genes share the same functions. In this study, we investigate the role of human CES1 in the development of steatohepatitis or dyslipidemia in C57BL/6 mice. Hepatocyte‐specific expression of human CES1 prevented Western diet or alcohol‐induced steatohepatitis and hyperlipidemia. Mechanistically, human CES1 induced lipolysis and fatty acid oxidation, leading to a reduction in hepatic triglyceride and free fatty acid levels. Human CES1 also reduced hepatic‐free cholesterol levels and induced low‐density lipoprotein receptor. In addition, human CES1 induced hepatic lipoprotein lipase and apolipoprotein C‐II expression. Conclusion: Hepatocyte‐specific overexpression of human CES1 attenuates diet‐induced steatohepatitis and hyperlipidemia.

Pig Liver Esterases Hydrolyze Endocannabinoids and Promote Inflammatory Response

“…Carboxylesterases have been established to play critical roles in drug metabolism and detoxifications (1,2). Emerging evidence, nonetheless, has linked the action of these hydrolases to lipid metabolism/processing (3,4,(10)(11)(12)(13)(14)(15)(16)(17)(18). Many lipid species and their precursors are signaling molecules, pointing to regulatory involvement of these hydrolases.…”

“…This superfamily includes structurally similar enzymes such as lipases. For many years, carboxylesterases have been recognized to have lipase activity (10)(11)(12)(13)(14)(15)(16)(17)(18). Indeed, several carboxylesterases have been shown to hydrolyze triglycerides and cholesterol esters (11,12).…”

Downregulation of Keap1 Confers Features of a Fasted Metabolic State

“…Ces1g-knockout mice have reduced energy expenditure, increased lipogenesis, and postprandial hyperlipidemia due to increased secretion of chylomicrons, whereas Ces1g overexpression leads to increased FAO and reduced hepatic triglyceride levels ( Quiroga et al., 2012 ; Xu et al., 2014 ). Most recently, it was shown that hepatocyte-specific overexpression of human CES1 in mice promotes FAO and attenuates high-fat/high-cholesterol/high-fructose diet- or alcohol-induced hepatic steatosis, inflammation, fibrosis, and hyperlipidemia, strongly suggesting a protective role of hepatic CES1 against metabolic disorders ( Xu et al., 2020 ). Taken together with our findings of the regulation of CES1 by Nrf2, it can be concluded that one mechanism by which Nrf2 activation protects against metabolic disorders is through induction of CES1.…”

Lipolysis: cellular mechanisms for lipid mobilization from fat stores

“…CES1 preferably hydrolyses CEs and TGs 236,237 . Hepatocyte-specific overexpression of human CES1 in transgenic mice increases hepatic TG hydrolase activity; lowers TG, FA and cholesterol content; and reduces reactive oxygen species (ROS), apoptosis and inflammation, which cumulatively protect mice from western-diet-or alcohol-induced steatohepatitis 238 . Both hepatocyte- 239 and macrophage-specific 240 overexpression of CES1 in mice decrease atherosclerosis susceptibility in LDL-receptor-deficient mice and, consistent with this finding, treatment of THP-1 macrophages with a CES1 inhibitor caused accumulation of CE 241 .…”