High glucose and hyperinsulinemia stimulate connective... : Hepatology (original) (raw)

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

Paradis, Valerie M.D.*,1,2; Perlemuter, Gabriel3; Bonvoust, Franck2; Dargere, Delphine2; Parfait, Beatrice4; Vidaud, Michel4; Conti, Marc5; Huet, Stephane6; Ba, Nathalie1; Buffet, Catherine3; Bedossa, Pierre1, 2

1Service d'Anatomie Pathologique, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France

2CNRS UPRES-A8067, Faculté de Pharmacie, Paris V, France

3Service d'Hépatologie, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France

4Laboratoire de Génétique Moléculaire JE 2195, Faculté de Pharmacie, Paris V, France

5Laboratoire de Biochimie, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France

6Centre de Recherche Glaxo Wellcome, Les Ulis, France.

E-mail: [email protected]

*Address reprint requests to: Service d'Anatomie Pathologique, Hôpital de Bicêtre, 78, rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, France. fax: (33) 1-45-21-32-81

Received March 28, 2001; accepted July 23, 2001; previously published online December 30, 2003

Abstract

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.