High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: A potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) may progress to liver fibrosis and cirr hosis. Mechanisms directly involved in the development of fibrosis have bee n poorly investigated. Because connective tissue growth factor (CTGF) is an intermediate key molecule involved in the pathogenesis of fibrosing chroni c liver diseases and is potentially induced by hyperglycemia, the aims of t his study were to (1) study the expression of CTGF in vivo both in human li ver biopsy specimens of patients with NASH and in an experimental model of obesity and type II diabetes (Zucker rats); and (2) analyze the effects of hyperglycemia and insulin in vitro on hepatic stellate cells, In vivo, CTGF overexpression was observed in the liver tissue of all of the 16 patients with NASH. CTGF immunostaining was mild in 7 cases (44%) and moderate or st rong in 9 cases (56%). Staining was mainly detected in the liver extracellu lar matrix in parallel with the amount of liver fibrosis. Liver from fa/fa rats also showed CTGF overexpression by comparison with Fa/fa rats both at the messenger RNA (mRNA) level (3-fold increase) and protein level. In vitr o, both CTGF mRNA and protein were significantly increased when hepatic ste llate cells were incubated with either glucose or insulin. A slight increas e in type I procollagen mRNA level was also observed in hepatic stellate ce lls incubated with glucose. In conclusion, this study suggests that hypergl ycemia and insulin are key-factors in the progression of fibrosis in patien ts with NASH through the upregulation of CTGF.