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J Biol Chem. 2016 Jun 3;291(23):12161-70. doi: 10.1074/jbc.M116.720631. Epub 2016 Mar 21.

Propionate Increases Hepatic Pyruvate Cycling and Anaplerosis and Alters Mitochondrial Metabolism.

Author information

1
From the Departments of Internal Medicine.
2
From the Departments of Internal Medicine, The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen DK 1017, Denmark.
3
Radiology and Biomedical Imaging, and the Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06519, and.
4
From the Departments of Internal Medicine, Cellular and Molecular Physiology, and richard.kibbey@yale.edu.
5
From the Departments of Internal Medicine, The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen DK 1017, Denmark Cellular and Molecular Physiology, and the Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06519, gerald.shulman@yale.edu.

Abstract

In mammals, pyruvate kinase (PK) plays a key role in regulating the balance between glycolysis and gluconeogenesis; however, in vivo regulation of PK flux by gluconeogenic hormones and substrates is poorly understood. To this end, we developed a novel NMR-liquid chromatography/tandem-mass spectrometry (LC-MS/MS) method to directly assess pyruvate cycling relative to mitochondrial pyruvate metabolism (VPyr-Cyc/VMito) in vivo using [3-(13)C]lactate as a tracer. Using this approach, VPyr-Cyc/VMito was only 6% in overnight fasted rats. In contrast, when propionate was infused simultaneously at doses previously used as a tracer, it increased VPyr-Cyc/VMito by 20-30-fold, increased hepatic TCA metabolite concentrations 2-3-fold, and increased endogenous glucose production rates by 20-100%. The physiologic stimuli, glucagon and epinephrine, both increased hepatic glucose production, but only glucagon suppressed VPyr-Cyc/VMito These data show that under fasting conditions, when hepatic gluconeogenesis is stimulated, pyruvate recycling is relatively low in liver compared with VMito flux and that liver metabolism, in particular pyruvate cycling, is sensitive to propionate making it an unsuitable tracer to assess hepatic glycolytic, gluconeogenic, and mitochondrial metabolism in vivo.

KEYWORDS:

epinephrine; glucagon; gluconeogenesis; isotopic tracer; liver metabolism; pyruvate kinase

PMID:
27002151
PMCID:
PMC4933266
DOI:
10.1074/jbc.M116.720631
[Indexed for MEDLINE]
Free PMC Article
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