Pioglitazone improves hepatic mitochondrial function in a mouse model of nonalcoholic steatohepatitis

Am J Physiol Endocrinol Metab. 2018 Aug 1;315(2):E163-E173. doi: 10.1152/ajpendo.00023.2018. Epub 2018 Apr 10.


Pioglitazone is effective in improving insulin resistance and liver histology in patients with nonalcoholic steatohepatitis (NASH). Because dysfunctional mitochondrial metabolism is a central feature of NASH, we hypothesized that an important target of pioglitazone would be alleviating mitochondrial oxidative dysfunction. To this end, we studied hepatic mitochondrial metabolism in mice fed high-fructose high-transfat diet (TFD) supplemented with pioglitazone for 20 wk, using nuclear magnetic resonance-based 13C isotopomer analysis. Pioglitazone improved whole body and adipose insulin sensitivity in TFD-fed mice. Furthermore, pioglitazone reduced intrahepatic triglyceride content and fed plasma ketones and hepatic TCA cycle flux, anaplerosis, and pyruvate cycling in mice with NASH. This was associated with a marked reduction in most intrahepatic diacylglycerol classes and, to a lesser extent, some ceramide species (C22:1, C23:0). Considering the cross-talk between mitochondrial function and branched-chain amino acid (BCAA) metabolism, pioglitazone's impact on plasma BCAA profile was determined in a cohort of human subjects. Pioglitazone improved the plasma BCAA concentration profile in patients with NASH. This appeared to be related to an improvement in BCAA degradation in multiple tissues. These results provide evidence that pioglitazone-induced changes in NASH are related to improvements in hepatic mitochondrial oxidative dysfunction and changes in whole body BCAA metabolism.

Keywords: insulin resistance; lipidomics; liver metabolism; mitochondria; nonalcoholic fatty liver disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Amino Acids, Branched-Chain / metabolism
  • Animals
  • Citric Acid Cycle / drug effects
  • Diet
  • Female
  • Fructose / toxicity
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Insulin Resistance
  • Ketones / blood
  • Male
  • Mice, Inbred C57BL
  • Middle Aged
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / metabolism*
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Pioglitazone / pharmacology*
  • Pioglitazone / therapeutic use
  • Pyruvic Acid / metabolism


  • Amino Acids, Branched-Chain
  • Hypoglycemic Agents
  • Ketones
  • Fructose
  • Pyruvic Acid
  • Pioglitazone