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Mol Metab. 2017 Nov;6(11):1468-1479. doi: 10.1016/j.molmet.2017.09.002. Epub 2017 Sep 18.

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

Author information

1
Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
2
AIRC Division of Metabolic Mechanisms of Disease, The University of Southwestern Texas Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, The University of Southwestern Texas Medical Center, Dallas, TX 75390, USA.
3
Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
4
Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
5
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Metabolomics Core Research Facility, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
6
Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of the Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: eric-taylor@uiowa.edu.

Abstract

OBJECTIVE:

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.

METHOD:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

Diabetes; Fibrosis; Gluconeogenesis; Inflammation; Liver; Mitochondrial pyruvate carrier (MPC)

PMID:
29107293
PMCID:
PMC5681281
DOI:
10.1016/j.molmet.2017.09.002
[Indexed for MEDLINE]
Free PMC Article

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