Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE−/− mice

// Nemanja Vujic 1 , Melanie Korbelius 1 , Christina Leopold 1 , Madalina Duta-Mare 1 , Silvia Rainer 1 , Stefanie Schlager 1 , Madeleine Goeritzer 1 , Dagmar Kolb 2 , Thomas O. Eichmann 3 , Clemens Diwoky 4, 7 , Andreas Zimmer 5, 6 , Robert Zimmermann 3, 6 , Achim Lass 3, 6 , Branislav Radovic 1, 6 , Dagmar Kratky 1, 6 1 Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria 2 Center for Medical Research, Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria 3 Institute of Molecular Biosciences, University of Graz, Graz, Austria 4 Institute of Biomedical Engineering, Graz University of Technology, Graz, Austria 5 Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria 6 BioTechMed, Graz, Austria 7 Current address: Institute of Molecular Biosciences, University of Graz, Graz, Austria Correspondence to: Dagmar Kratky, email: dagmar.kratky@medunigraz.at Keywords: endocannabinoid, cannabinoid receptor, desensitization, lipolysis, cholesterol Received: December 28, 2016 Accepted: March 14, 2017 Published: March 23, 2017 ABSTRACT Monoglyceride lipase (MGL) hydrolyzes monoglycerides (MGs) to glycerol and fatty acids. Among various MG species MGL also degrades 2-arachidonoylglycerol (2-AG), the most abundant endocannabinoid and potent activator of cannabinoid receptors (CBR) 1 and 2. MGL-knockout (−/−) mice exhibit pronounced 2-AG accumulation, but lack central cannabimimetic effects due to CB1R desensitization. We have previously shown that MGL affects plaque stability in apolipoprotein E (ApoE)−/− mice, an established animal model for dyslipidemia and atherosclerosis. In the current study, we investigated functional consequences of MGL deficiency on lipid and energy metabolism in ApoE/MGL double knockout (DKO) mice. MGL deficiency affected hepatic cholesterol metabolism by causing increased cholesterol elimination via the biliary pathway. Moreover, DKO mice exhibit lipid-triggered delay in gastric emptying without major effects on overall triglyceride and cholesterol absorption. The observed phenotype of DKO mice is likely not a consequence of potentiated CB1R signaling but rather dependent on the activation of alternative signaling pathways. We conclude that MGL deficiency causes complex metabolic changes including cholesterol metabolism and regulation of gut transit independent of the endocannabinoid system.