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Cell Metab. 2005 Jul;2(1):55-65.

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

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1
Howard Hughes Medical Institute, Department of Internal Medicine, Yale University School of Medicine, New Haven, CN 06520, USA.

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.

PMID:
16054099
DOI:
10.1016/j.cmet.2005.06.006
[Indexed for MEDLINE]
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