Hepatic Mitochondrial Pyruvate Carrier 1 Is Required for Efficient Regulation of Gluconeogenesis and Whole-Body Glucose Homeostasis

Lawrence R Gray; Mst Rasheda Sultana; Adam J Rauckhorst; Lalita Oonthonpan; Sean C Tompkins; Arpit Sharma; Xiaorong Fu; Ren Miao; Alvin D Pewa; Kathryn S Brown; Erin E Lane; Ashley Dohlman; Diana Zepeda-Orozco; Jianxin Xie; Jared Rutter; Andrew W Norris; James E Cox; Shawn C Burgess; Matthew J Potthoff; Eric B Taylor

doi:10.1016/j.cmet.2015.07.027

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Hepatic Mitochondrial Pyruvate Carrier 1 Is Required for Efficient Regulation of Gluconeogenesis and Whole-Body Glucose Homeostasis

Journal article

Open access

Peer reviewed

Hepatic Mitochondrial Pyruvate Carrier 1 Is Required for Efficient Regulation of Gluconeogenesis and Whole-Body Glucose Homeostasis

Lawrence R Gray, Mst Rasheda Sultana, Adam J Rauckhorst, Lalita Oonthonpan, Sean C Tompkins, Arpit Sharma, Xiaorong Fu, Ren Miao, Alvin D Pewa, Kathryn S Brown, …

Cell metabolism, Vol.22(4), pp.669-681

10/06/2015

DOI: 10.1016/j.cmet.2015.07.027

PMCID: PMC4754674

PMID: 26344103

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Abstract

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.

Proprotein Convertase 1 - genetics

Gluconeogenesis - drug effects

Glutamine - metabolism

Male

Hepatocytes - metabolism

Hepatocytes - cytology

Triglycerides - analysis

Acrylates - pharmacology

Diet, High-Fat

Pyruvic Acid - metabolism

Obesity - etiology

Glycogen - analysis

Hyperglycemia - prevention & control

Proprotein Convertase 2 - metabolism

Proprotein Convertase 1 - metabolism

Liver - metabolism

Mice, Inbred C57BL

Cells, Cultured

Citric Acid Cycle - drug effects

Proprotein Convertase 1 - deficiency

Mitochondria, Liver - enzymology

Mice, Knockout

Obesity - metabolism

Hyperglycemia - metabolism

Animals

Proprotein Convertase 2 - genetics

Proprotein Convertase 2 - antagonists & inhibitors

Glucose - metabolism

Mice

Details

Title: Subtitle: Hepatic Mitochondrial Pyruvate Carrier 1 Is Required for Efficient Regulation of Gluconeogenesis and Whole-Body Glucose Homeostasis
Creators: Lawrence R Gray - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
Mst Rasheda Sultana - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
Adam J Rauckhorst - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
Lalita Oonthonpan - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
Sean C Tompkins - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
Arpit Sharma - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
Xiaorong Fu - Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Ren Miao - Metabolomics Core Research Facility, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Alvin D Pewa - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
Kathryn S Brown - Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
Erin E Lane - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Fraternal Order of the Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
Ashley Dohlman - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
Diana Zepeda-Orozco - Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Fraternal Order of the Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
Jianxin Xie - Cell Signaling Technology, Inc., Danvers, MA 01923, USA
Jared Rutter - Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA
Andrew W Norris - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Fraternal Order of the Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
James E Cox - 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
Shawn C Burgess - Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Matthew J Potthoff - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Fraternal Order of the Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA
Eric B Taylor - Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Fraternal Order of the Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA; Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA. Electronic address: eric-taylor@uiowa.edu
Resource Type: Journal article
Publication Details: Cell metabolism, Vol.22(4), pp.669-681
DOI: 10.1016/j.cmet.2015.07.027
PMID: 26344103
PMCID: PMC4754674
NLM abbreviation: Cell Metab
ISSN: 1550-4131
eISSN: 1932-7420
Publisher: United States
Grant note: F32 DK101183 / NIDDK NIH HHS R01 DK104998 / NIDDK NIH HHS R01 DK078184 / NIDDK NIH HHS T32 CA078586 / NCI NIH HHS P01 DK058398 / NIDDK NIH HHS T32 HL007638 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS R00 AR059190 / NIAMS NIH HHS R01 GM094232 / NIGMS NIH HHS P30 CA086862 / NCI NIH HHS GM007337 / NIGMS NIH HHS R24 DK096518 / NIDDK NIH HHS T32 HL007121 / NHLBI NIH HHS P30CA086862 / NCI NIH HHS
Language: English
Date published: 10/06/2015
Academic Unit: Molecular Physiology and Biophysics; Endocrinology and Diabetes; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
Record Identifier: 9984024524402771

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