After three weeks on a high-fat diet, mice lacking mtGPAT1 had markedly lower than normal concentrations of the liver lipid metabolites hepatic triacylglycerol and diacylglycerol, the researchers reported. Compared to normal mice, the animals also were protected from hepatic insulin resistance.
Surprisingly, Shulman said, mice lacking mtGPAT1 exhibited increased hepatic insulin sensitivity despite an almost 2-fold elevation in hepatic acyl-CoA concentrations, a compound which had also been implicated in insulin resistance previously. The finding suggests that long chain acyl-CoAs do not mediate fat-induced hepatic insulin resistance.
"Protection of fat-induced hepatic insulin resistance was correlated with reduced concentrations of diacylglycerol in the liver and reduced activation of protein kinase C[epsilon]. Diacylglycerol is an important activator of protein kinase C[epsilon] and previous studies by the Shulman group have implicated activation of this kinase in hepatic insulin resistance," he explained.
"Taken together, these data implicate diacylglycerol in the liver as an important trigger in causing fat-induced hepatic insulin resistance," Shulman said. "These data also suggest that mtGPAT1 might be a potent therapeutic target to treat hepatic steatosis and hepatic insulin resistance," he added.