title: Inhibiting monoacylglycerol acyltransferase 1 ameliorates hepatic metabolic abnormalities but not inflammation and injury in mice.
abstract: Abnormalities in hepatic lipid metabolism and insulin action are believed to play a critical role in the etiology of nonalcoholic steatohepatitis. Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis, and knocking down Mogat1 improves glucose metabolism and hepatic insulin signaling, but whether increased MGAT activity plays a role in the etiology of nonalcoholic steatohepatitis is unclear. To examine this issue, mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were injected with antisense oligonucleotides (ASOs) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. The HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver and adipose tissue, attenuated weight gain, improved glucose tolerance, improved hepatic insulin signaling, and decreased hepatic triacylglycerol content compared with control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic diacylglycerol, cholesterol, or free fatty acid content; improve histologic measures of liver injury; or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves hepatic metabolic abnormalities without attenuating liver inflammation and injury.
authors.affiliation: From the Departments of Pediatrics, Medicine, and.
authors.forename: Nisreen
authors.initials: N
authors.lastname: Soufi
authors.affiliation: Medicine, and.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Hall
authors.affiliation: Medicine, and.
authors.forename: Zhouji
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Medicine, and.
authors.forename: Jun
authors.initials: J
authors.lastname: Yoshino
authors.affiliation: Medicine, and.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Collier
authors.affiliation: Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri 63110.
authors.forename: James C
authors.initials: JC
authors.lastname: Mathews
authors.affiliation: Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri 63110.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Brunt
authors.affiliation: the Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri 63104, and.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Albert
authors.affiliation: ISIS Pharmaceuticals Inc., Carlsbad, California 92008.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: the Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri 63104, and.
authors.forename: David A
authors.initials: DA
authors.lastname: Ford
authors.affiliation: Medicine, and bfinck@dom.wustl.edu.
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D004032:Diet; D004075:Diglycerides; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000473:pathology; D006706:Homeostasis; D007249:Inflammation / Q000473:pathology*; D007962:Leukocytes / Q000187:drug effects / Q000473:pathology; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D017351:N-Acetylglucosaminyltransferases; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: C011439:1,2-diacylglycerol; D015415:Biomarkers; D004075:Diglycerides; D005227:Fatty Acids; D016376:Oligonucleotides, Antisense; D014280:Triglycerides; D000217:Acyltransferases; C459903:MGAT1 protein, mouse; D017351:N-Acetylglucosaminyltransferases; D005947:Glucose
keywords: Diacylglycerol; Fatty Acid Metabolism; Inflammation; Insulin Resistance; Liver; Nonalcoholic Steatohepatitis