Abstract
Homocysteine metabolism is altered in diabetic patients. Cystathionine beta-synthase (CBS), a key enzyme involved in the transsulfuration pathway, which irreversibly converts homocysteine to cysteine, catalyzes the condensation of serine and homocysteine to cystathionine. Studies in streptozotocin-induced diabetic rats have shown that CBS enzyme activity is elevated in the liver but not in the kidney, and this effect is reversed by insulin treatment. To determine whether these effects resulted from alterations at the level of gene transcription, CBS mRNA was measured in diabetic and insulin-treated diabetic rats. CBS mRNA levels were found to be markedly higher in streptozotocin-induced diabetic rat livers; these were reduced by insulin administration. In H4IIE cells, a rat hepatoma cell culture model, glucocorticoids increased the cellular levels of CBS enzyme protein and CBS mRNA; insulin inhibited this stimulatory effect. Treatment with insulin also decreased CBS levels in HepG2 cells, a human hepatoma cell line. Nuclear run-on experiments in the rat cells confirmed that stimulation of CBS gene expression by glucocorticoids and the inhibition by insulin occurred at the transcriptional level. Transient transfections of HepG2 cells with a CBS-1b promoter luciferase reporter construct showed that the promoter activity was decreased by 70% after insulin treatment. These results show that insulin has a direct role in regulating homocysteine metabolism. Altered insulin levels in diseases such as diabetes may influence homocysteine metabolism by regulating the hepatic transsulfuration pathway.
Highlights
Homocysteine metabolism is altered in diabetic patients
CBS mRNA levels were higher in diabetic rat livers compared with control rat livers, and this was reversed by insulin treatment (Fig. 1B)
It is clear that homocysteine metabolism is impaired in diabetic patients [15, 33]
Summary
Homocysteine metabolism is altered in diabetic patients. Cystathionine -synthase (CBS), a key enzyme involved in the transsulfuration pathway, which irreversibly converts homocysteine to cysteine, catalyzes the condensation of serine and homocysteine to cystathionine. Studies in streptozotocin-induced diabetic rats have shown that CBS enzyme activity is elevated in the liver but not in the kidney, and this effect is reversed by insulin treatment. Transient transfections of HepG2 cells with a CBS-1b promoter luciferase reporter construct showed that the promoter activity was decreased by 70% after insulin treatment These results show that insulin has a direct role in regulating homocysteine metabolism. Our previous work has shown that the plasma homocysteine level was decreased in the streptozotocin-induced rat diabetic model with a concomitant increase in hepatic CBS enzyme activity; insulin administration reversed these effects [15]. The aim of this study was to examine the role of insulin and counterregulatory hormones on the expression of the CBS gene, using a diabetic rat liver model as well as rat and human hepatoma cell lines
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