The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity

Adam J Rauckhorst,Lawrence R Gray,Ryan D Sheldon,Xiaorong Fu,Alvin D Pewa,Charlotte R Feddersen,Adam J Dupuy,Katherine N Gibson-Corley,James E Cox,Shawn C Burgess,Eric B Taylor

doi:10.1016/j.molmet.2017.09.002

Abstract

ObjectiveExcessive hepatic gluconeogenesis is a defining feature of type 2 diabetes (T2D). Most gluconeogenic flux is routed through mitochondria. The mitochondrial pyruvate carrier (MPC) transports pyruvate from the cytosol into the mitochondrial matrix, thereby gating pyruvate-driven gluconeogenesis. Disruption of the hepatocyte MPC attenuates hyperglycemia in mice during high fat diet (HFD)-induced obesity but exerts minimal effects on glycemia in normal chow diet (NCD)-fed conditions. The goal of this investigation was to test whether hepatocyte MPC disruption provides sustained protection from hyperglycemia during long-term HFD and the differential effects of hepatocyte MPC disruption on TCA cycle metabolism in NCD versus HFD conditions. MethodWe utilized long-term high fat feeding, serial measurements of postabsorptive blood glucose and metabolomic profiling and 13C-lactate/13C-pyruvate tracing to investigate the contribution of the MPC to hyperglycemia and altered hepatic TCA cycle metabolism during HFD-induced obesity. ResultsHepatocyte MPC disruption resulted in long-term attenuation of hyperglycemia induced by HFD. HFD increased hepatic mitochondrial pyruvate utilization and TCA cycle capacity in an MPC-dependent manner. Furthermore, MPC disruption decreased progression of fibrosis and levels of transcript markers of inflammation. ConclusionsBy contributing to chronic hyperglycemia, fibrosis, and TCA cycle expansion, the hepatocyte MPC is a key mediator of the pathophysiology induced in the HFD model of T2D.

Highlights

Type 2 diabetes (T2D) is a complex disease with numerous derangements in systemic metabolism
Liver mitochondrial pyruvate carrier (MPC) disruption provides sustained protection from hyperglycemia To investigate the role of the hepatic MPC in hyperglycemia during long-term high fat feeding, littermate Mpc1fl/fl (WT) and Mpc1fl/fl þ Alb-Cre (MPC LivKO) mice were fed high fat diet (HFD) for 44 weeks
We observed that hepatocyte-specific MPC disruption exerts minimal to no effect on blood glucose in normal chow diet (NCD) fed mice but attenuates hyperglycemia in 12 weeks’ HFD fed mice [14]

Summary

Introduction

Type 2 diabetes (T2D) is a complex disease with numerous derangements in systemic metabolism. Many result from altered function of the liver, where ectopic lipid deposition leads to insulin resistance and excessive gluconeogenesis [1,2] This is often accompanied by progressive liver injury, in which fatty infiltration leads to inflammation and fibrosis, that may, in-turn, contribute to systemic inflammation [3]. Hepatocyte mitochondria play a special role in systemic metabolism During fasting, they provide energy for the whole body by supporting the synthesis of new glucose, in two key ways. They provide energy for the whole body by supporting the synthesis of new glucose, in two key ways They perform the initial reactions essential for channeling systemic pyruvate and amino acids into gluconeogenesis, gating flux.

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