Rat pancreatic level of cystathionine γ-lyase is regulated by glucose level via specificity protein 1 (SP1) phosphorylation

Cystathionine gamma-lyase (CSE) catalyses the endogenous production of hydrogen sulphide (H2S) in pancreatic beta cells, and H2S has been shown to inhibit insulin release from these cells. As altered pancreatic H2S production modulated by glucose has been previously shown, we hypothesised that the Cse gene could be regulated by glucose level in insulin-secreting cells. The effects of glucose on CSE protein level and mRNA level were analysed in INS-1E cells. Glucose effect on Cse promoter activity was tested by constructing a proximal Cse promoter vector including specificity protein 1 (Sp1) consensus sequence. High glucose (20 mmol/l) inhibited H2S production in INS-1E cells and freshly isolated rat pancreatic islets. Cse mRNA expression, CSE activity and protein abundance were also profoundly reduced by high glucose. The involvement of SP1 in basal and high-glucose-regulated CSE production was demonstrated. Sp1-knockdown abolished a large portion of CSE production at basal glucose. Phosphorylation of SP1 stimulated by high glucose was inhibited by p38 mitogen-activated protein kinase (MAPK) inhibitors SB203580 and SB202190. After blocking p38 MAPK phosphorylation, the inhibitive effects of high glucose on CSE protein production and promoter activity in INS-1E cells were also virtually abolished. Glucose stimulates the phosphorylation of SP1 via p38 MAPK activation, which leads to decreased Cse promoter activity and subsequent downregulation of Cse gene expression. Inhibited H2S production through glucose-mediated CSE activity and production alterations may be involved in the fine control of glucose-induced insulin secretion.