Endogenous liver carcinogenesis in the rat *

Abstract

Carcinogenesis may be effected not only through exposure to exogenous stimuli but also by genetic and epigenetic influences derived from endogenous factors. In the latter case, the mechanisms are still largely obscure because of the limited availability of appropriate in vivo experimental models. However, continuous feeding of a diet deficient in choline and methionine is well known to cause hepatocellular carcinomas (HCC) in rats in the absence of any known exogenous carcinogens and can serve as a good research model. A semi-synthetic, choline-deficient, L-amino acid-defined (CDAA) diet, containing practically no choline and low methionine, induces HCC with a background of fatty liver and hepatocyte death, subsequent regeneration and fibrosis resulting in cirrhosis. Using the CDAA diet, we have revealed the participation of oxidative injury to DNA and other subcellular components and of alteration in intrahepatic signal transduction pathways in the mechanisms underlying this rat liver carcinogenesis model. In the present paper, the current understanding of endogenous rat liver carcinogenesis, due to dietary choline deficiency, is reviewed.

Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease

“…The difference in the etiology of steatosis in these models gives a clue to the mechanism of action of FGF1. The ob/ob mice and DIO mice have increased hepatic lipid accumulation caused by excessive food intake, but a choline deficiency causes defective hepatic β-oxidation and the production of VLDL, resulting in steatosis in the absence of obesity or insulin resistance (10,28). These differences in the pathophysiology of steatosis were clearly reflected in the zonal distribution of lipids in these models.…”

Promotion Effect of a Choline-deficient L-amino Acid-defined (CDAA) Diet on Hepatocellular Foci Formation Initiated by Diethylnitrosamine in Fischer 344 Rats

“…8-OHG has been reported that to be produced in vitro study when the C-8 position of guanine residues in DNA is hydroxylated by various oxygen radical producing agents 37 . CDAA diet has been reported to induce linear increase in 8-OHG in liver cells from the first day of feeding 24 . Therefore, CDAA diet is thought to induce reactive oxygen species (ROS)-derived oxidative stress to rat liver, presumably by inflammatory cells such as Kupffer cells or hepatocytes 38 .…”

“…In constant with semipurified CD diet, CDAA diet has no contamination of carcinogens or choline. Therefore, it is thought that CDAA diet has a stronger effect to induce liver tumor than semipurified CD diet in rats [22][23][24] , and the effect of CDAA diet is caused entirely by an endogenous mechanism.…”

Epigenetic down-regulation of the suppressor of cytokine signaling 1 (Socs1) gene is associated with the STAT3 activation and development of hepatocellular carcinoma induced by methyl-deficiency in rats

“…18 In light of these considerations, the present study was undertaken to investigate the role of PDGFs, TGFβ, and STAT3 in the pathogenesis of HCC using a rat model of liver carcinogenesis induced by a methyl-deficient diet, which is remarkably relevant to the hepatocarcinogenesis in humans. 19,20 …”