期刊
CELL METABOLISM
卷 22, 期 4, 页码 669-681出版社
CELL PRESS
DOI: 10.1016/j.cmet.2015.07.027
关键词
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资金
- NIH [R01 DK104998, R00 AR059190, R01 DK078184, R24 DK096518, R01 GM094232, F32 DK101183, T32 HL007121, T32 HL007638, P30CA086862]
- Carver College of Medicine NIH [GM007337]
- Robert A. Welch Foundation [I-1804]
- FOEDRC Faculty Research Scholar
- Edward Mallinckrodt Jr. Foundation grant
- American Diabetes Association Junior Faculty Award
- Carver College of Medicine Collaborative Pilot Grant
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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