Pioglitazone rescues mitochondrial lipid remodeling and pyruvate dehydrogenase hyperactivation in hepatic insulin resistance

Alterations in hepatic mitochondrial function are a feature of type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) and may precipitate the development of fibrosis and steatohepatitis. Using multi-dimensional mass spectrometry-based shotgun lipidomics we show that livers of insulin-resistant obese mice display extensive remodeling of the mitochondrial lipid cardiolipin, which may increase susceptibility to oxidative stress. This is exacerbated by excessive mitochondrial fatty acid delivery, evidenced by long-chain acylcarnitine accumulation, and is accompanied by increased TCA cycle activity and hyperactivation of pyruvate dehydrogenase. Moreover, insulin-sensitization with pioglitazone rescued cardiolipin remodeling and reduced mitochondrial pyruvate metabolism by simultaneously suppressing pyruvate carboxylase flux and inhibiting PDH activation through PDK4 induction / PDP2 suppression. These pioglitazone-derived benefits were entirely dissociated from changes in hepatic triglyceride or diacylglyceride levels. Our findings identify targetable mitochondrial features of T2D and NAFLD and highlight the benefit of insulin sensitization in managing the clinical burden of obesity-associated disease.