Hepatic Mitochondrial Pyruvate Carrier 1 Is Required for Efficient Regulation of Gluconeogenesis and Whole-Body Glucose Homeostasis.
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.
Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
Lawrence R
LR
Gray
Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
Mst Rasheda
MR
Sultana
Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
Adam J
AJ
Rauckhorst
Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
Lalita
L
Oonthonpan
Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
Sean C
SC
Tompkins
Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
Arpit
A
Sharma
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.
Xiaorong
X
Fu
Metabolomics Core Research Facility, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Ren
R
Miao
Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
Alvin D
AD
Pewa
Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
Kathryn S
KS
Brown
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.
Erin E
EE
Lane
Department of Biochemistry, University of Iowa Carver College of Medicine, Iowa City, IA 52240, USA.
Ashley
A
Dohlman
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.
Diana
D
Zepeda-Orozco
Cell Signaling Technology, Inc., Danvers, MA 01923, USA.
Jianxin
J
Xie
Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Jared
J
Rutter
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.
Andrew W
AW
Norris
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.
James E
JE
Cox
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.
Shawn C
SC
Burgess
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.
Matthew J
MJ
Potthoff
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.
Eric B
EB
Taylor
D000179:Acrylates / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002952:Citric Acid Cycle / Q000187:drug effects; D059305:Diet, High-Fat; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D006003:Glycogen / Q000032:analysis; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism / Q000517:prevention & control; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000201:enzymology*; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D045664:Proprotein Convertase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D045706:Proprotein Convertase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D014280:Triglycerides / Q000032:analysis
D000179:Acrylates; D014280:Triglycerides; D005973:Glutamine; C043654:2-cyano-3-(1-phenylindol-3-yl)acrylate; D019289:Pyruvic Acid; D006003:Glycogen; C473656:Pcsk1 protein, mouse; D045664:Proprotein Convertase 1; C473668:Pcsk2 protein, mouse; D045706:Proprotein Convertase 2; D005947:Glucose