Decreased Gluconeogenesis in the Absence of Cystathionine Gamma-Lyase and the Underlying Mechanisms

Ashley A. Untereiner, Rui Wang, Youngjun Ju, Lingyun Wu

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

To investigate the regulation of hepatic glucose production by cystathionine γ-lyase (CSE)-generated hydrogen sulfide (H2S) in hepatic glucose production under physiological conditions. Results: We found that CSE knockout (KO) mice had a reduced rate of gluconeogenesis, which was reversed by administration of NaHS (an H2S donor) (i.p.). Interestingly, isolated CSE KO hepatocytes exhibited a reduced glycemic response to chemical-induced activation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and glucocorticoid pathways compared with wild-type (WT) hepatocytes. Treatment with the inhibitors for PKA (KT5720) or glucocorticoid receptor (GR) (RU-486) significantly reduced H2S-stimulated glucose production from both WT and CSE KO mouse hepatocytes. NaHS treatment upregulated the protein levels of key gluconeogenic transcription factors, such as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and CCAAT-enhancer-binding protein-β (C/EBP-β). Moreover, exogenous H2S augmented the S-sulfhydration of the rate-limiting gluconeogenic enzymes and PGC-1α and increased their activities, which were lower in untreated CSE KO hepatocytes. Finally, knockdown of PGC-1α, but not C/EBP-β, significantly decreased NaHS-induced glucose production from the primary hepatocytes. Innovation: This study demonstrates the stimulatory effect of endogenous H2S on liver glucose production and reveals three underlying mechanisms; that is, H2S upregulates the expression levels of PGC-1α and phosphoenolpyruvate carboxykinase via the GR pathway; H2S upregulates the expression level of PGC-1α through the activation of the cAMP/PKA pathway as well as PGC-1α activity via S-sulfhydration; and H2S upregulates the expression and the activities (by S-sulfhydration) of glucose-6-phosphatase and fructose-1,6-bisphosphatase. Conclusion: This study may offer clues for the homeostatic regulation of glucose metabolism under physiological conditions and its dysregulation in metabolic syndrome.

Original languageEnglish (US)
Pages (from-to)129-140
Number of pages12
JournalAntioxidants and Redox Signaling
Volume24
Issue number3
DOIs
StatePublished - Jan 20 2016
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry

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