title: Monoglyceride lipase deficiency affects hepatic cholesterol metabolism and lipid-dependent gut transit in ApoE-/- mice.
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.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Nemanja
authors.initials: N
authors.lastname: Vujic
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Melanie
authors.initials: M
authors.lastname: Korbelius
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Leopold
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Madalina
authors.initials: M
authors.lastname: Duta-Mare
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rainer
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schlager
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Goeritzer
authors.affiliation: Center for Medical Research, Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kolb
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Eichmann
authors.affiliation: Institute of Biomedical Engineering, Graz University of Technology, Graz, Austria.|Current address: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Clemens
authors.initials: C
authors.lastname: Diwoky
authors.affiliation: Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria.|BioTechMed, Graz, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.|BioTechMed, Graz, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Zimmermann
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.|BioTechMed, Graz, Austria.
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.|BioTechMed, Graz, Austria.
authors.forename: Branislav
authors.initials: B
authors.lastname: Radovic
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.|BioTechMed, Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D001095:Arachidonic Acids / Q000378:metabolism; D001212:Asialoglycoproteins / Q000172:deficiency / Q000235:genetics*; D050197:Atherosclerosis / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism; D055786:Gene Knockout Techniques; D005989:Glycerides / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice
chemical_list: D001057:Apolipoproteins E; D001095:Arachidonic Acids; D001212:Asialoglycoproteins; C064720:Clec10a protein, mouse; D063388:Endocannabinoids; D005989:Glycerides; D037181:Lectins, C-Type; D008565:Membrane Proteins; C094503:glyceryl 2-arachidonate; D002784:Cholesterol; D000429:Alcohol Oxidoreductases; C555915:carbonyl reductase 1, mouse
keywords: cannabinoid receptor; cholesterol; desensitization; endocannabinoid; lipolysis