title: Propionate Increases Hepatic Pyruvate Cycling and Anaplerosis and Alters Mitochondrial Metabolism.
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.
authors.affiliation: From the Departments of Internal Medicine.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Perry
authors.affiliation: From the Departments of Internal Medicine.
authors.forename: Candace B
authors.initials: CB
authors.lastname: Borders
authors.affiliation: From the Departments of Internal Medicine.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.affiliation: From the Departments of Internal Medicine.
authors.forename: Xian-Man
authors.initials: XM
authors.lastname: Zhang
authors.affiliation: From the Departments of Internal Medicine.
authors.forename: Tiago C
authors.initials: TC
authors.lastname: Alves
authors.affiliation: From the Departments of Internal Medicine, The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen DK 1017, Denmark.
authors.forename: Kitt Falk
authors.initials: KF
authors.lastname: Petersen
authors.affiliation: Radiology and Biomedical Imaging, and the Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06519, and.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Rothman
authors.affiliation: From the Departments of Internal Medicine, Cellular and Molecular Physiology, and richard.kibbey@yale.edu.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Kibbey
authors.affiliation: 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.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002853:Chromatography, Liquid; D002952:Citric Acid Cycle / Q000187:drug effects*; D004837:Epinephrine / Q000097:blood / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D005934:Glucagon / Q000097:blood / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology*; D019289:Pyruvic Acid / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
chemical_list: D001786:Blood Glucose; D007328:Insulin; D011422:Propionates; D019289:Pyruvic Acid; D005934:Glucagon; D005947:Glucose; D004837:Epinephrine
keywords: epinephrine; glucagon; gluconeogenesis; isotopic tracer; liver metabolism; pyruvate kinase