Propionate increases hepatic pyruvate cycling and anaplerosis and alters mitochondrial metabolism
Open accessAbstract
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.
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Supraphysiologic propionate administration increases TCA cycle metabolite pools in the liver and induces hepatic gluconeogenesis.
“Supraphysiologic propionate administration increases TCA cycle metabolite pools in the liver and induces hepatic gluconeogenesis (96), but the degree to which cells can activate propionyl-CoA catabolism to sustain anaplerotic flux under physiologic conditions remains largely unknown.”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [96]
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Regulation and function of the mammalian tricarboxylic acid cycle
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“Supraphysiologic propionate administration increases TCA cycle metabolite pools in the liver and induces hepatic gluconeogenesis (96), but the degree to which cells can activate propionyl-CoA catabolism to sustain anaplerotic flux under physiologic conditions remains largely unknown.”
BackgroundCompartmentalised acyl-CoA metabolism and roles in chromatin regulation
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- Authors
- Perry, R. J., Borders, C. B., Cline, G. W., Zhang, X.-M., Alves, T. C., Petersen, K. F., Rothman, D. L., Kibbey, R. G., & Shulman, G. I.
- Affiliations
- Yale University (US)
- University of Copenhagen (DK)
- Corresponding author
- Kibbey, Richard G.
- Shulman, Gerald I.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 291
- Issue
- 23
- Pages
- 12161-12170
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4933266
- OpenAlex
- W2309835329
- Cited by
- 78
- References
- 28
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 4 · 2022: 12 · 2021: 9 · 2020: 11 · 2019: 7 · 2018: 5 · 2017: 7 · 2016: 4
- FWCI
- 3.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Funders
- National Institutes of Health (R01 DK-40936, P30 DK-45735, U24 DK-059635, T32 DK-101019, R01 DK-056886, R01 DK-092606)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK-093959)
- National Institute on Aging (R01 AG-23686)
- National Institute of Neurological Disorders and Stroke (R01 NS-087568)
- National Center for Advancing Translational Sciences (UL1 TR-000142)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- propionate, anaplerosis, mitochondrial metabolism, hepatic gluconeogenesis, pyruvate kinase, endogenous glucose production, glucagon, epinephrine, fasting, TCA cycle metabolites
- MeSH terms
- Animals, Blood Glucose, Chromatography, Liquid, Citric Acid Cycle, Epinephrine, Glucagon, Gluconeogenesis, Glucose, Glycolysis, Insulin, Liver, Gas Chromatography-Mass Spectrometry, Mitochondria, Propionates, Rats, Sprague-Dawley, Pyruvic Acid, Tandem Mass Spectrometry, Metabolic Networks and Pathways
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