Premium
High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: A potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis
Author(s) -
Paradis Valerie,
Perlemuter Gabriel,
Bonvoust Franck,
Dargere Delphine,
Parfait Beatrice,
Vidaud Michel,
Conti Marc,
Huet Stephane,
Ba Nathalie,
Buffet Catherine,
Bedossa Pierre
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.28055
Subject(s) - ctgf , hepatic stellate cell , medicine , fibrosis , endocrinology , connective tissue , cirrhosis , steatohepatitis , hepatic fibrosis , liver biopsy , growth factor , insulin , biology , hyperinsulinemia , pathology , insulin resistance , fatty liver , biopsy , receptor , disease
Nonalcoholic steatohepatitis (NASH) may progress to liver fibrosis and cirrhosis. Mechanisms directly involved in the development of fibrosis have been poorly investigated. Because connective tissue growth factor (CTGF) is an intermediate key molecule involved in the pathogenesis of fibrosing chronic liver diseases and is potentially induced by hyperglycemia, the aims of this study were to (1) study the expression of CTGF in vivo both in human liver 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 strong in 9 cases (56%). Staining was mainly detected in the liver extracellular 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 vitro , both CTGF mRNA and protein were significantly increased when hepatic stellate cells were incubated with either glucose or insulin. A slight increase in type I procollagen mRNA level was also observed in hepatic stellate cells incubated with glucose. In conclusion, this study suggests that hyperglycemia and insulin are key‐factors in the progression of fibrosis in patients with NASH through the up‐regulation of CTGF.