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

S Neschen, K Morino, LE Hammond, D Zhang, ZX Liu… - Cell metabolism, 2005 - cell.com
S Neschen, K Morino, LE Hammond, D Zhang, ZX Liu, AJ Romanelli, GW Cline…
Cell metabolism, 2005cell.com
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 …
Summary
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 PKCϵ 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.
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