Enhanced expression of growth factors and imbalance between hepatocyte proliferation and apoptosis in the livers of rats fed a choline-deficient, ?-amino acid-defined diet

Abstract

Abstract In a rat model of hepatocarcinogenesis induced by a choline-deficient, l -amino acid-defined (CDAA) diet, hepatocellular carcinoma (HCC) occurs in conjunction with fatty liver, hepatocyte injury and regeneration, fibrosis and cirrhosis. This is similar to human HCC development with cirrhosis. The aim of this study is to clarify sequential changes in the expression of growth and growth inhibitory factors, and hepatocyte proliferation and apoptosis during development of preneoplastic nodules in rats fed a CDAA diet. The expression of hepatocyte growth factor was stimulated at about the same time as CDAA diet-induced liver injury within 1 week. Hepatocyte growth factor reached a maximum level of expression from 4 to 8 weeks. Transforming growth factor (TGF)-α expression increased from 4 to 40 weeks. Although TGF-β, a growth inhibitory factor for hepatocytes, was also expressed with a peak from 4 to 8 weeks followed by a gradual decrease until 48 weeks, expression of cyclin D1 and hepatocyte proliferation continued to be stimulated throughout the experimental period. Additionally, the number of apoptotic hepatocytes was markedly reduced after peaking at 8 weeks. These results suggest that some hepatocytes in the livers of rats fed a CDAA diet may escape from TGF-β-induced growth inhibition and apoptosis, leading to development of preneoplastic nodules.