Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice

Cell Metab. 2005 Jul;2(1):55-65. doi: 10.1016/j.cmet.2005.06.006.

Abstract

In order to investigate the role of mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 (mtGPAT1) in the pathogenesis of hepatic steatosis and hepatic insulin resistance, we examined whole-body insulin action in awake mtGPAT1 knockout (mtGPAT1(-/-)) and wild-type (wt) mice after regular control diet or three weeks of high-fat feeding. In contrast to high-fat-fed wt mice, mtGPAT1(-/-) mice displayed markedly lower hepatic triacylglycerol and diacylglycerol concentrations and were protected from hepatic insulin resistance possibly due to a lower diacylglycerol-mediated PKC activation. Hepatic acyl-CoA has previously been implicated in the pathogenesis of insulin resistance. Surprisingly, compared to wt mice, mtGPAT1(-/-) mice exhibited increased hepatic insulin sensitivity despite an almost 2-fold elevation in hepatic acyl-CoA content. These data suggest that mtGPAT1 might serve as a novel target for treatment of hepatic steatosis and hepatic insulin resistance and that long chain acyl-CoA's do not mediate fat-induced hepatic insulin resistance in this model.

Publication types

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

MeSH terms

  • AMP-Activated Protein Kinases
  • Acetyl Coenzyme A / metabolism
  • Acetyl-CoA Carboxylase / metabolism
  • Animals
  • Dietary Fats / administration & dosage
  • Dietary Fats / pharmacology
  • Diglycerides / metabolism
  • Fasting
  • Fatty Liver / enzymology*
  • Fatty Liver / genetics
  • Fatty Liver / prevention & control*
  • Glucose Tolerance Test
  • Glycerol-3-Phosphate O-Acyltransferase / deficiency*
  • Glycerol-3-Phosphate O-Acyltransferase / genetics
  • Glycerol-3-Phosphate O-Acyltransferase / metabolism
  • Insulin Resistance / genetics*
  • Liver / cytology
  • Liver / enzymology*
  • Liver / metabolism
  • Liver / pathology
  • Lysophospholipids / metabolism
  • Male
  • Malonyl Coenzyme A / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / enzymology*
  • Mitochondria / genetics
  • Multienzyme Complexes / metabolism
  • Phenotype
  • Protein-Serine-Threonine Kinases / metabolism
  • Triglycerides / metabolism

Substances

  • Dietary Fats
  • Diglycerides
  • Lysophospholipids
  • Multienzyme Complexes
  • Triglycerides
  • Malonyl Coenzyme A
  • Acetyl Coenzyme A
  • Glycerol-3-Phosphate O-Acyltransferase
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase