Hepatic mitochondrial pyruvate carrier 1 is required for efficient regulation of gluconeogenesis and whole-body glucose homeostasis

Lawrence R. Gray, Mst Rasheda Sultana, Adam J. Rauckhorst, Lalita Oonthonpan, Sean C. Tompkins, Arpit Sharma, Xiaorong Fu, Ren Miao, Alvin D. Pewa, Kathryn S. Brown, Erin E. Lane, Ashley Dohlman, Diana Zepeda-Orozco, Jianxin Xie, Jared Rutter, Andrew W. Norris, James E. Cox, Shawn C. Burgess, Matthew J. Potthoff, Eric B. Taylor

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

Gluconeogenesis is critical for maintenance of euglycemia during fasting. Elevated gluconeogenesis during type 2 diabetes (T2D) contributes to chronic hyperglycemia. Pyruvate is a major gluconeogenic substrate and requires import into the mitochondrial matrix for channeling into gluconeogenesis. Here, we demonstrate that the mitochondrial pyruvate carrier (MPC) comprising the Mpc1 and Mpc2 proteins is required for efficient regulation of hepatic gluconeogenesis. Liver-specific deletion of Mpc1 abolished hepatic MPC activity and markedly decreased pyruvate-driven gluconeogenesis and TCA cycle flux. Loss of MPC activity induced adaptive utilization of glutamine and increased urea cycle activity. Diet-induced obesity increased hepatic MPC expression and activity. Constitutive Mpc1 deletion attenuated the development of hyperglycemia induced by a high-fat diet. Acute, virally mediated Mpc1 deletion after diet-induced obesity decreased hyperglycemia and improved glucose tolerance. We conclude that the MPC is required for efficient regulation of gluconeogenesis and that the MPC contributes to the elevated gluconeogenesis and hyperglycemia in T2D.

Original languageEnglish (US)
Pages (from-to)669-681
Number of pages13
JournalCell Metabolism
Volume22
Issue number4
DOIs
StatePublished - Oct 6 2015

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Gray, L. R., Sultana, M. R., Rauckhorst, A. J., Oonthonpan, L., Tompkins, S. C., Sharma, A., Fu, X., Miao, R., Pewa, A. D., Brown, K. S., Lane, E. E., Dohlman, A., Zepeda-Orozco, D., Xie, J., Rutter, J., Norris, A. W., Cox, J. E., Burgess, S. C., Potthoff, M. J., & Taylor, E. B. (2015). Hepatic mitochondrial pyruvate carrier 1 is required for efficient regulation of gluconeogenesis and whole-body glucose homeostasis. Cell Metabolism, 22(4), 669-681. https://doi.org/10.1016/j.cmet.2015.07.027