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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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AMP-Activated Protein Kinases
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Acetyl Coenzyme A / metabolism
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Acetyl-CoA Carboxylase / metabolism
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Animals
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Dietary Fats / administration & dosage
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Dietary Fats / pharmacology
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Diglycerides / metabolism
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Fasting
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Fatty Liver / enzymology*
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Fatty Liver / genetics
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Fatty Liver / prevention & control*
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Glucose Tolerance Test
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Glycerol-3-Phosphate O-Acyltransferase / deficiency*
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Glycerol-3-Phosphate O-Acyltransferase / genetics
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Glycerol-3-Phosphate O-Acyltransferase / metabolism
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Insulin Resistance / genetics*
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Liver / cytology
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Liver / enzymology*
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Liver / metabolism
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Liver / pathology
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Lysophospholipids / metabolism
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Male
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Malonyl Coenzyme A / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitochondria / enzymology*
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Mitochondria / genetics
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Multienzyme Complexes / metabolism
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Phenotype
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Protein Serine-Threonine Kinases / metabolism
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Triglycerides / metabolism
Substances
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Dietary Fats
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Diglycerides
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Lysophospholipids
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Multienzyme Complexes
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Triglycerides
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Malonyl Coenzyme A
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Acetyl Coenzyme A
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Glycerol-3-Phosphate O-Acyltransferase
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Protein Serine-Threonine Kinases
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AMP-Activated Protein Kinases
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Acetyl-CoA Carboxylase