Open AccessIntestine‐Specific Overexpression of Carboxylesterase 2c Protects Mice From Diet‐Induced Liver Steatosis and Obesity
Author(s) -
Maresch Lisa Katharina,
Benedikt Pia,
Feiler Ursula,
Eder Sandra,
Zierler Kathrin A.,
Taschler Ulrike,
Kolleritsch Stephanie,
Eichmann Thomas O.,
Schoiswohl Gabriele,
Leopold Christina,
Wieser Beatrix I.,
Lackner Caroline,
Rülicke Thomas,
van Klinken Jan,
Kratky Dagmar,
Moustafa Tarek,
Hoefler Gerald,
Haemmerle Guenter
Publication year - 2019
Publication title -
hepatology communications
Language(s) - English
Resource type - Journals
ISSN - 2471-254X
DOI - 10.1002/hep4.1292
Subject(s) - chylomicron , endocrinology , medicine , lipid metabolism , steatosis , small intestine , biology , adipose tissue , nonalcoholic fatty liver disease , lipolysis , fatty liver , lipid droplet , monoacylglycerol lipase , chemistry , biochemistry , cholesterol , very low density lipoprotein , lipoprotein , disease , endocannabinoid system , receptor
Murine hepatic carboxylesterase 2c ( Ces2c ) and the presumed human ortholog carboxylesterase 2 ( CES2 ) have been implicated in the development of nonalcoholic fatty liver disease (NAFLD) in mice and obese humans. These studies demonstrated that Ces2c hydrolyzes triglycerides (TGs) in hepatocytes. Interestingly, Ces2c / CES2 is most abundantly expressed in the intestine, indicating a role of Ces2c / CES2 in intestinal TG metabolism. Here we show that Ces2c is an important enzyme in intestinal lipid metabolism in mice. Intestine‐specific Ces2c overexpression (Ces2c int ) provoked increased fatty acid oxidation (FAO) in the small intestine accompanied by enhanced chylomicron clearance from the circulation. As a consequence, high‐fat diet–fed Ces2c int mice were resistant to excessive diet‐induced weight gain and adipose tissue expansion. Notably, intestinal Ces2c overexpression increased hepatic insulin sensitivity and protected mice from NAFLD development. Although lipid absorption was not affected in Ces2c int mice, fecal energy content was significantly increased. Mechanistically, we demonstrate that Ces2c is a potent neutral lipase, which efficiently hydrolyzes TGs and diglycerides (DGs) in the small intestine, thereby generating fatty acids (FAs) for FAO and monoglycerides (MGs) and DGs for potential re‐esterification. Consequently, the increased availability of MGs and DGs for re‐esterification and primordial apolipoprotein B 48 particle lipidation may increase chylomicron size, ultimately mediating more efficient chylomicron clearance from the circulation. Conclusion: This study suggests a critical role for Ces2c in intestinal lipid metabolism and highlights the importance of intestinal lipolysis to protect mice from the development of hepatic insulin resistance, NAFLD, and excessive diet‐induced weight gain during metabolic stress.