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

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 upregulation of CTGF. (HEPATOLOGY 2001;34:738-744.)

Elevated Serum Insulin is an Independent Risk Factor for Hepatocellular Carcinoma: A Case Control Study from Nepal

“…IR encourage fibrosis succession, progress of hepatic steatosis, hyperleptinemia, increased TNF production and abridged expression of peroxisome proliferator activated receptors (Hsu et al, 2008). The increased levels of insulin and glucose possibly will endorse fibrogenesis by stimulating the liberation of connective tissue growth factor from hepatic stellate cells (Paradis et al, 2001). Conclusion: The effect of an insulin level in increasing HCC risk was consistent and influences incidence, risk of recurrence, overall survival, and treatment-related complications in HCC patients.…”

Role of free radicals in liver diseases

“…Insulin can damage the liver directly and indirectly [122,123]. Patients with long-term ambulatory dialysis develop fatty liver, but only when insulin is added to the peritoneal fluid dialysate [124][125][126]. The steatosis is seen only at the surface of the liver and sometimes has the histological appearance of NASH [124].…”

Obesity and liver disease

“…82 Finally, a recent study suggested that hyperglycaemia and insulin are key factors in the progresson of fibrosis in patients with NASH through the upregulation of connective tissue growth factor. 83 Three recent studies including obese patients have identified several clinical and laboratory features that predict the presence of NASH and/or fibrosis, and thus the possible progression to cirrhosis. The first study included 93 mildly obese patients (BMI > 25 kg/m 2 ) being investigated for abnormal liver blood tests.…”