title: Novel role of a triglyceride-synthesizing enzyme: DGAT1 at the crossroad between triglyceride and cholesterol metabolism.
abstract: Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is a key enzyme in triacylglycerol (TG) biosynthesis. Here we show that genetic deficiency and pharmacological inhibition of DGAT1 in mice alters cholesterol metabolism. Cholesterol absorption, as assessed by acute cholesterol uptake, was significantly decreased in the small intestine and liver upon DGAT1 deficiency/inhibition. Ablation of DGAT1 in the intestine (I-DGAT1(-/-)) alone is sufficient to cause these effects. Consequences of I-DGAT1 deficiency phenocopy findings in whole-body DGAT1(-/-) and DGAT1 inhibitor-treated mice. We show that deficiency/inhibition of DGAT1 affects cholesterol metabolism via reduced chylomicron size and increased trans-intestinal cholesterol excretion. These effects are independent of cholesterol uptake at the apical surface of enterocytes but mediated through altered dietary fatty acid metabolism. Our findings provide insight into a novel role of DGAT1 and identify a pathway by which intestinal DGAT1 deficiency affects whole-body cholesterol homeostasis in mice. Targeting intestinal DGAT1 may represent a novel approach for treating hypercholesterolemia.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Vinay
authors.initials: V
authors.lastname: Sachdev
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Leopold
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Raimund
authors.initials: R
authors.lastname: Bauer
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z 4H4, Canada.
authors.forename: Jay V
authors.initials: JV
authors.lastname: Patankar
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center, 11203 New York, United States.
authors.forename: Jahangir
authors.initials: J
authors.lastname: Iqbal
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Sascha
authors.initials: S
authors.lastname: Obrowsky
authors.affiliation: Departments of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9713 Groningen, The Netherlands.
authors.forename: Renze
authors.initials: R
authors.lastname: Boverhof
authors.affiliation: Departments of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9713 Groningen, The Netherlands.
authors.forename: Marcela
authors.initials: M
authors.lastname: Doktorova
authors.affiliation: Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Scheicher
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Goeritzer
authors.affiliation: Institute of Cell Biology, Histology, and Embryology, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kolb
authors.affiliation: AstraZeneca R&D, 431 50 Moelndal, Sweden.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Turnbull
authors.affiliation: Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.affiliation: Institute of Pathology, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.affiliation: Department of Cell Biology, SUNY Downstate Medical Center, 11203 New York, United States.
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
authors.affiliation: Departments of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9713 Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria. Electronic address: dagmar.kratky@medunigraz.at.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D051048:Diacylglycerol O-Acyltransferase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D004041:Dietary Fats; D005227:Fatty Acids / Q000378:metabolism; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000378:metabolism; D007408:Intestinal Absorption / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D014280:Triglycerides; D002784:Cholesterol; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase
keywords: Cholesterol absorption; Chylomicron size; DGAT1 inhibition; Intestinal DGAT1 deficiency; Trans-intestinal cholesterol excretion