Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Maresch, LK.
Deciphering the role of Ces2c in intestinal lipid metabolism and whole-body energy homeostasis.
[ Dissertation ] University of Graz; 2019. pp.177.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Kratky Dagmar
- Moustafa Tarek
- Altmetrics:
- Abstract:
- Previous studies have implicated murine hepatic carboxylesterase 2c (Ces2c) and the assumed human ortholog carboxylesterase 2 (CES2) in nonalcoholic fatty liver disease (NAFLD) development in obese mice and humans. We and others have demonstrated that Ces2c is an efficient hepatic triglyceride (TG) hydrolase. Notably, Ces2c/CES2 exhibits high expression levels in the small intestine, suggesting a role for Ces2c/CES2 in intestinal TG catabolism. Here we show that intestinal Ces2c is an important player in whole-body lipid and energy metabolism in mice. Intestinal Ces2c overexpression (Ces2cint) augmented fatty acid oxidation (FAO) in the small intestine and enhanced chylomicron clearance from the circulation. Consequently, Ces2cint mice were protected from excessive diet-induced weight gain and adipose tissue expansion on high-fat diet (HFD). Interestingly, intestine-specific Ces2c overexpression elevated hepatic insulin sensitivity and prevented NAFLD development on HFD. Even though lipid absorption was normal in HFD-fed Ces2cint mice, fecal energy content was drastically augmented. Mechanistically, we show that Ces2c is a highly efficient, intestinal TG and diglyceride (DG) hydrolase. Fatty acids (FAs) generated by Ces2c are preferentially used as substrate for FAO while monoglycerides (MGs) and DGs may be used as substrate for TG re-esterification and subsequent chylomicron assembly. Because of elevated TG availability in enterocytes of Ces2c transgenic mice, primordial apolipoprotein B48 (apoB48) particle may acquire more TG, leading to an increase in chylomicron size, ultimately mediating enhanced chylomicron clearance. My study highlights the important role of intestinal Ces2c in whole-body energy homeostasis and demonstrates the importance of intestinal lipid metabolism in preventing the development of hepatic insulin resistance, NAFLD and excessive diet-induced weight gain during metabolic stress.