The mitochondrial dicarboxylate carrier mediates in vivo hepatic gluconeogenesis

Pape, D. J.; Falls-Hubert, K. C.; Merrill, R. A.; Ahmed, A.; Qian, Q.; McGivney, G. R.; Sobieralski, P.; Rauckhorst, A. J.; Yang, L.; Taylor, E. B.

doi:10.1101/2024.09.12.612761

bioRxiv · 10.1101/2024.09.12.612761

The mitochondrial dicarboxylate carrier mediates in vivo hepatic gluconeogenesis

Pape, D. J.·Falls-Hubert, K. C.·Merrill, R. A.·Ahmed, A.·Qian, Q.·McGivney, G. R.·Sobieralski, P.·Rauckhorst, A. J.·Yang, L.·Taylor, E. B.

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Abstract

Hepatic gluconeogenesis (GNG) is essential for maintaining euglycemia during prolonged fasting. However, GNG becomes pathologically elevated and drives chronic hyperglycemia in type 2 diabetes (T2D). Lactate/pyruvate is a major GNG substrate known to be imported into mitochondria for GNG. Yet, the subsequent mitochondrial carbon export mechanisms required to supply the extra-mitochondrial canonical GNG pathway have not been genetically delineated. Here, we evaluated the role of the mitochondrial dicarboxylate carrier (DiC) in mediating GNG from lactate/pyruvate. We generated liver-specific DiC knockout (DiC LivKO) mice. During lactate/pyruvate tolerance tests, DiC LivKO decreased plasma glucose excursion and 13C-lactate/-pyruvate flux into hepatic and plasma glucose. In a Western diet (WD) feeding model of T2D, acute DiC LivKO after induction of obesity decreased lactate/pyruvate-driven GNG, hyperglycemia, and hyperinsulinemia. Our results show that mitochondrial carbon export through the DiC mediates GNG and that the DiC contributes to impaired glucose homeostasis in a mouse model of T2D.

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Pape, D. J., Falls-Hubert, K. C., Merrill, R. A., Ahmed, A., Qian, Q., McGivney, G. R., Sobieralski, P., Rauckhorst, A. J., Yang, L., Taylor, E. B.. 2024-09-13. The mitochondrial dicarboxylate carrier mediates in vivo hepatic gluconeogenesis. https://doi.org/10.1101/2024.09.12.612761

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