• Ling Zhang, Guangdong Yang, Ashley Untereiner, Youngjun Ju, Lingyun Wu, and Rui Wang.
• Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada P7B 5E1.
• Endocrinology. 2013 Jan 1; 154 (1): 114-26.

AbstractMounting evidence has established hydrogen sulfide (H(2)S) as an important gasotransmitter with multifaceted physiological functions. The aim of the present study was to investigate the role of H(2)S on glucose utilization, glycogen synthesis, as well as gluconeogenesis in both HepG(2) cells and primary mouse hepatocytes. Incubation with NaHS (a H(2)S donor) impaired glucose uptake and glycogen storage in HepG(2) cells via decreasing glucokinase activity. Adenovirus-mediated cystathionine γ-lyase (CSE) overexpression increased endogenous H(2)S production and lowered glycogen content in HepG(2) cells. Glycogen content was significantly higher in liver tissues from CSE knockout (KO) mice compared to that from wild type (WT) mice in fed condition. Glucose consumption was less in primarily cultured hepatocytes isolated from WT mice than those from CSE KO mice, but more glucose was produced by hepatocytes via gluconeogenesis and glycogenolysis pathways in WT mice than in CSE KO mice. NaHS treatment reduced the phosphorylation of AMP-activated protein kinase, whereas stimulation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside reversed H(2)S-impaired glucose uptake. H(2)S-increased glucose production was likely through increased phosphoenolpyruvate carboxykinase activity. In addition, insulin at the physiological range inhibited CSE expression, and H(2)S decreased insulin-stimulated phosphorylation of Akt in HepG(2) cells. CSE expression was increased, however, in insulin-resistant state induced by exposing cells to high levels of insulin (500 nm) and glucose (33 mm) for 24 h. Taken together, these data suggest that the interaction of H(2)S and insulin in liver plays a pivotal role in regulating insulin sensitivity and glucose metabolism.

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