Propionate Increases Hepatic Pyruvate Cycling and Anaplerosis and Alters Mitochondrial Metabolism

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Chromatography, Liquid
  • Citric Acid Cycle / drug effects*
  • Epinephrine / blood
  • Epinephrine / pharmacology
  • Gas Chromatography-Mass Spectrometry
  • Glucagon / blood
  • Glucagon / pharmacology
  • Gluconeogenesis / drug effects
  • Glucose / metabolism
  • Glycolysis / drug effects
  • Insulin / blood
  • Liver / drug effects*
  • Liver / metabolism
  • Metabolic Networks and Pathways / drug effects*
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Propionates / administration & dosage
  • Propionates / pharmacology*
  • Pyruvic Acid / metabolism*
  • Rats, Sprague-Dawley
  • Tandem Mass Spectrometry

Substances

  • Blood Glucose
  • Insulin
  • Propionates
  • Pyruvic Acid
  • Glucagon
  • Glucose
  • Epinephrine