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

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

Journal article

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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, …

Molecular metabolism (Germany), Vol.6(11), pp.1468-1479

11/2017

DOI: 10.1016/j.molmet.2017.09.002

PMCID: PMC5681281

PMID: 29107293

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Abstract

Excessive 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. We 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. Hepatocyte 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. By 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. [Display omitted] •Hepatic MPC disruption protects from hyperglycemia during long-term HFD.•HFD increases TCA cycle metabolite pool capacity and flux.•Hepatic MPC disruption abrogates HFD-induced TCA cycle expansion.

Inflammation

Diabetes

Mitochondrial pyruvate carrier (MPC)

Liver

Fibrosis

Gluconeogenesis

Details

Title: Subtitle: The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity
Creators: Adam J Rauckhorst - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Lawrence R Gray - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Ryan D Sheldon - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Xiaorong Fu - AIRC Division of Metabolic Mechanisms of Disease, The University of Southwestern Texas Medical Center, Dallas, TX 75390, USA
Alvin D Pewa - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Charlotte R Feddersen - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Adam J Dupuy - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Katherine N Gibson-Corley - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
James E Cox - Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Shawn C Burgess - AIRC Division of Metabolic Mechanisms of Disease, The University of Southwestern Texas Medical Center, Dallas, TX 75390, USA
Eric B Taylor - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Molecular metabolism (Germany), Vol.6(11), pp.1468-1479
DOI: 10.1016/j.molmet.2017.09.002
PMID: 29107293
PMCID: PMC5681281
NLM abbreviation: Mol Metab
ISSN: 2212-8778
eISSN: 2212-8778
Publisher: Elsevier GmbH
Grant note: name: NIH, award: R01 DK104998, R00 AR059190, R01 DK078184; DOI: 10.13039/100000928, name: Robert A. Welch Foundation, award: I-1804, F32 DK101183, T32 HL007121, T32 HL007638, T32 HL007344, T32 GM067795, P30CA086862
Language: English
Date published: 11/2017
Academic Unit: Molecular Physiology and Biophysics; Anatomy and Cell Biology; Pathology; Fraternal Order of Eagles Diabetes Research Center; Ophthalmology and Visual Sciences
Record Identifier: 9984025472602771

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