Abstract
Carboxylesterase 2 (CES2/Ces2) proteins exert established roles in (pro)drug metabolism. Recently, human and murine CES2/Ces2c have been discovered as triglyceride (TG) hydrolases implicated in the development of obesity and fatty liver disease. The murine Ces2 family consists of seven homologous genes as opposed to a single CES2 gene in humans. However, the mechanistic role of Ces2 protein family members is not completely understood. In this study, we examined activities of all Ces2 members toward TGs, diglycerides (DGs), and monoglycerides (MGs) as the substrate. Besides CES2/Ces2c, we measured significant TG hydrolytic activities for Ces2a, Ces2b, and Ces2e. Notably, these Ces2 members and CES2 efficiently hydrolyzed DGs and MGs, and their activities even surpassed those measured for TG hydrolysis. The localization of CES2/Ces2c proteins at the ER may implicate a role of these lipases in lipid signaling pathways. We found divergent expression of Ces2 genes in the liver and intestine of mice on a high-fat diet, which could relate to changes in lipid signaling. Finally, we demonstrate reduced CES2 expression in the colon of patients with inflammatory bowel disease and a similar decline in Ces2 expression in the colon of a murine colitis model. Together, these results demonstrate that CES2/Ces2 members are highly efficient DG and MG hydrolases that may play an important role in liver and gut lipid signaling.
Highlights
Dysregulated lipid metabolism commonly contributes to the development of metabolic disease
Of nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide ranging from benign hepatic steatosis to nonalcoholic steatohepatitis (NASH), which can further progress to liver cirrhosis [1, 2]
Because purified Ces2/carboxylesterase 2 (CES2) proteins exhibited potent neutral lipid hydrolase activities, we evaluated whether mRNA expression levels were divergently affected by changes in lipid homeostasis caused by metabolic stress such as high-fat diet (HFD) feeding or fasting
Summary
Dysregulated lipid metabolism commonly contributes to the development of metabolic disease. Human CES2 is expressed in various metabolic organs including the liver, intestine, and kidney and is well known to be involved in the detoxification or metabolic activation of various xenobiotics including drugs, environmental toxicants, and carcinogens [8]. CES2/Ces2c expression is decreased in the liver of obese humans and mice [6, 10]. Ces2c knockdown causes liver steatosis, whereas overexpression of CES2/Ces2c reverses liver steatosis and improves glucose tolerance on high-fat diet (HFD) [10]. We recently showed that intestine-specific Ces2c overexpression counteracts diet-induced obesity and NAFLD in mice possibly via increasing the chylomicron particle size, which likely accelerates chylomicron lipid uptake in muscles [9]. Cells were harvested 48 h after transfection (except for Ces2h: cells were harvested 24 h after transfection) and lysed by sonication in ice-cold buffer A (250 mM sucrose, 1 mM EDTA, 1 mM dithiothreitol, 20 μg/ml leupeptin, 2 μg/ml antipain, 1 μg /ml pepstatin; pH 7.0)
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