Inhibiting monoacylglycerol acyltransferase 1 ameliorates hepatic metabolic abnormalities but not inflammation and injury in mice

J Biol Chem. 2014 Oct 24;289(43):30177-88. doi: 10.1074/jbc.M114.595850. Epub 2014 Sep 11.

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.

Keywords: Diacylglycerol; Fatty Acid Metabolism; Inflammation; Insulin Resistance; Liver; Nonalcoholic Steatohepatitis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / antagonists & inhibitors*
  • Acyltransferases / metabolism
  • Adipose Tissue / drug effects
  • Adipose Tissue / enzymology
  • Adipose Tissue / pathology
  • Adiposity / drug effects
  • Animals
  • Biomarkers / metabolism
  • Diet
  • Diglycerides
  • Fatty Acids / metabolism
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Glucose / metabolism
  • Glucose Tolerance Test
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / pathology
  • Homeostasis
  • Inflammation / pathology*
  • Leukocytes / drug effects
  • Leukocytes / pathology
  • Lipogenesis / drug effects
  • Lipogenesis / genetics
  • Liver / drug effects
  • Liver / enzymology
  • Liver / metabolism*
  • Liver / pathology*
  • Male
  • Mice, Inbred C57BL
  • Mice, Obese
  • N-Acetylglucosaminyltransferases
  • Oligonucleotides, Antisense / administration & dosage
  • Oligonucleotides, Antisense / pharmacology
  • Oxidation-Reduction / drug effects
  • Triglycerides / metabolism
  • Weight Gain / drug effects

Substances

  • 1,2-diacylglycerol
  • Biomarkers
  • Diglycerides
  • Fatty Acids
  • Oligonucleotides, Antisense
  • Triglycerides
  • Acyltransferases
  • MGAT1 protein, mouse
  • N-Acetylglucosaminyltransferases
  • Glucose