title: Decreased Gluconeogenesis in the Absence of Cystathionine Gamma-Lyase and the Underlying Mechanisms.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  This study may offer clues for the homeostatic regulation of glucose metabolism under physiological conditions and its dysregulation in metabolic syndrome.
authors.affiliation: 1 The Cardiovascular and Metabolic Research Unit, Lakehead University , Ontario, Canada .|2 Department of Health Sciences, Lakehead University , Ontario, Canada .|3 Thunder Bay Regional Research Institute , Ontario, Canada .
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Untereiner
authors.affiliation: 1 The Cardiovascular and Metabolic Research Unit, Lakehead University , Ontario, Canada .|4 Department of Biology, Laurentian University , Ontario, Canada .
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: 1 The Cardiovascular and Metabolic Research Unit, Lakehead University , Ontario, Canada .|5 Department of Kinesiology, Lakehead University , Ontario, Canada .
authors.forename: YoungJun
authors.initials: Y
authors.lastname: Ju
authors.affiliation: 1 The Cardiovascular and Metabolic Research Unit, Lakehead University , Ontario, Canada .|2 Department of Health Sciences, Lakehead University , Ontario, Canada .|3 Thunder Bay Regional Research Institute , Ontario, Canada .
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D002227:Carbazoles / Q000008:administration & dosage; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000235:genetics / Q000378:metabolism*; D005943:Gluconeogenesis / Q000235:genetics*; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011758:Pyrroles / Q000008:administration & dosage; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D002227:Carbazoles; C545013:Cebpb protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011758:Pyrroles; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; C057416:KT 5720; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D003542:Cystathionine gamma-Lyase; D005947:Glucose; D006862:Hydrogen Sulfide