The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity

Adam J. Rauckhorst, Lawrence R. Gray, Ryan D. Sheldon, Xiaorong Fu, Alvin D. Pewa, Charlotte R. Feddersen, Adam J. Dupuy, Katherine N. Gibson-Corley, James E. Cox, Shawn C. Burgess, Eric B. Taylor

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Objective Excessive hepatic gluconeogenesis is a defining feature of type 2 diabetes (T2D). Most gluconeogenic flux is routed through mitochondria. The mitochondrial pyruvate carrier (MPC) transports pyruvate from the cytosol into the mitochondrial matrix, thereby gating pyruvate-driven gluconeogenesis. Disruption of the hepatocyte MPC attenuates hyperglycemia in mice during high fat diet (HFD)-induced obesity but exerts minimal effects on glycemia in normal chow diet (NCD)-fed conditions. The goal of this investigation was to test whether hepatocyte MPC disruption provides sustained protection from hyperglycemia during long-term HFD and the differential effects of hepatocyte MPC disruption on TCA cycle metabolism in NCD versus HFD conditions. Method We utilized long-term high fat feeding, serial measurements of postabsorptive blood glucose and metabolomic profiling and 13C-lactate/13C-pyruvate tracing to investigate the contribution of the MPC to hyperglycemia and altered hepatic TCA cycle metabolism during HFD-induced obesity. Results Hepatocyte MPC disruption resulted in long-term attenuation of hyperglycemia induced by HFD. HFD increased hepatic mitochondrial pyruvate utilization and TCA cycle capacity in an MPC-dependent manner. Furthermore, MPC disruption decreased progression of fibrosis and levels of transcript markers of inflammation. Conclusions By contributing to chronic hyperglycemia, fibrosis, and TCA cycle expansion, the hepatocyte MPC is a key mediator of the pathophysiology induced in the HFD model of T2D.

Original languageEnglish (US)
Pages (from-to)1468-1479
Number of pages12
JournalMolecular Metabolism
Volume6
Issue number11
DOIs
StatePublished - Nov 1 2017

Keywords

  • Diabetes
  • Fibrosis
  • Gluconeogenesis
  • Inflammation
  • Liver
  • Mitochondrial pyruvate carrier (MPC)

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Rauckhorst, A. J., Gray, L. R., Sheldon, R. D., Fu, X., Pewa, A. D., Feddersen, C. R., Dupuy, A. J., Gibson-Corley, K. N., Cox, J. E., Burgess, S. C., & Taylor, E. B. (2017). The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity. Molecular Metabolism, 6(11), 1468-1479. https://doi.org/10.1016/j.molmet.2017.09.002