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 (Ces2cint) 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 Ces2cint 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 Ces2cint 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 B48 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.