@article{ae669cbe9995408da2acb7137cb5eee0,
title = "Hepatic mitochondrial pyruvate carrier 1 is required for efficient regulation of gluconeogenesis and whole-body glucose homeostasis",
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.",
author = "Gray, {Lawrence R.} and Sultana, {Mst Rasheda} and Rauckhorst, {Adam J.} and Lalita Oonthonpan and Tompkins, {Sean C.} and Arpit Sharma and Xiaorong Fu and Ren Miao and Pewa, {Alvin D.} and Brown, {Kathryn S.} and Lane, {Erin E.} and Ashley Dohlman and Diana Zepeda-Orozco and Jianxin Xie and Jared Rutter and Norris, {Andrew W.} and Cox, {James E.} and Burgess, {Shawn C.} and Potthoff, {Matthew J.} and Taylor, {Eric B.}",
note = "Funding Information: We thank Brett Wagner and the Radiation and Free Radical Research Core Facility for assistance running the Seahorse Bioscience XF96, Jamie Soto and Jianrong Yao of the Fraternal Order of the Eagles Diabetes Research Center (FOEDRC) Metabolic Phenotypic Core for assistance with insulin clamps, and Charles Brenner and Brandon Davies of the Department of Biochemistry for carefully reading a draft manuscript and providing helpful feedback. This work was supported by NIH grants R01 DK104998 (E.B.T.); R00 AR059190 (E.B.T.); R01 DK078184 (S.C.B.); R24 DK096518 (A.W.N.); R01 GM094232 (J.R.); F32 DK101183 (L.R.G.); T32 HL007121 to Francois Abboud (L.R.G.); T32 HL007638 to Michael Welsh (A.J.R.); P30CA086862 to George Weiner, which contributed to support of core facilities utilized for this research; the Carver College of Medicine NIH-funded MSTP Training Program grant GM007337 (S.C.T.); Robert A. Welch Foundation grant I-1804 (S.C.B.); a FOEDRC Faculty Research Scholar (A.W.N.); an Edward Mallinckrodt Jr. Foundation grant (M.J.P.); an American Diabetes Association Junior Faculty Award (M.J.P.); and a Carver College of Medicine Collaborative Pilot Grant (E.B.T. and M.J.P.). Jianxin Xie is an employee of Cell Signaling Technology, Inc. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = oct,
day = "6",
doi = "10.1016/j.cmet.2015.07.027",
language = "English (US)",
volume = "22",
pages = "669--681",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "4",
}