Hepatic Mitochondrial Pyruvate Carrier 1 Is Required for Efficient Regulation of Gluconeogenesis and Whole-Body Glucose Homeostasis

Cell Metabolism
Lawrence R GrayEric B Taylor

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.

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Citations

Jan 31, 2016·Biochimica Et Biophysica Acta·Tom Bender, Jean-Claude Martinou
Feb 14, 2016·Trends in Biochemical Sciences·Kristofor A OlsonJared Rutter
Jun 9, 2016·Current Opinion in Genetics & Development·Adam J Rauckhorst, Eric B Taylor
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Dec 18, 2016·The FEBS Journal·Christopher E ShannonLuke Norton
Apr 20, 2018·The Biochemical Journal·Eunjin KohKyung-Sup Kim
May 25, 2016·Molecular and Cellular Biology·Caitlyn E BowmanMichael J Wolfgang
Nov 6, 2018·The Journal of Biological Chemistry·Brian D FinkWilliam I Sivitz
Jan 8, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Logan K TownsendDavid C Wright
Sep 26, 2019·Physiological Reports·Santhosh KaranthAmnon Schlegel
Oct 19, 2019·Behavioural Pharmacology·Debapriya GarabaduSahil Sharma
May 15, 2019·Applied Physiology, Nutrition, and Metabolism = Physiologie Appliquée, Nutrition Et Métabolisme·Kehinde Samuel Olaniyi, Lawrence Aderemi Olatunji
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Jan 30, 2016·The Journal of Biological Chemistry·Lawrence R GrayEric B Taylor
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Sep 22, 2019·Brain Sciences·Bor Luen Tang
Jul 28, 2020·Biomolecules·Joséphine ZangariJean-Claude Martinou

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