|Chavez, Pollyanna R. -|
|Chung, Jayong -|
|Liu, Chun -|
|Paiva, Sergio A. -|
|Seitz, Helmut K. -|
|Wang, Xiang-Dong -|
|Lian, Fuzhi -|
Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: March 7, 2011
Publication Date: April 13, 2011
Citation: Chavez, P., Chung, J., Liu, C., Paiva, S., Seitz, H., Wang, X., Lian, F. 2011. Long term ethanol consumption promotes hepatic tumorigenesis but impairs normal hepatocyte proliferation in rats. Journal of Nutrition. 141(6):1049-1055 PMID 21490289. Interpretive Summary: Until now, the question of whether alcohol could promote carcinogenesis by its own action or whether it did so by acting as cofactor in the presence of other risk factors has not been well defined. By eliminating these other factors from our model, we were able to show that alcohol can act as a promoter in liver cancer development, independent of any role in carcinogen activation or tumor initiation and uncomplicated by viral infection, inadequate diet, or partial hepatectomy of the liver. We report here the results of long-term ethanol feeding for six and ten months with a nutritionally adequate liquid diet in a chemically-initiated carcinogenic rat model. Importantly, we observe an impaired growth of normal liver cells alongside increased tumor formation, which are characterized by decreased cellular proliferation, accompanied by adenoma formation in alcohol fed rats. Further the alcohol-impaired hepatocyte growth was associated with reduced plasma levels of insulin like growth factor-1, an essential anabolic agent for cell growth. We concluded that this model of alcohol-promoted liver cancer development is a good model for studying dietary intervention against alcohol-related hepatic carcinogenesis.
Technical Abstract: Chronic and excessive alcohol consumption has been related to an increased risk of several cancers, including that of the liver; however, studies in animal models have yet to conclusively determine whether ethanol acts as a tumor promoter in hepatic tumorigenesis. We examined whether prolonged alcohol consumption could act as a hepatic tumor promoter after initiation by diethylnitrosamine (DEN) in a rat model. Male Sprague-Dawley rats were injected with 20 mg DEN/kg body weight 1 wk before introduction of either an ethanol liquid diet or an isoenergic control liquid diet. Hepatic pathological lesions, hepatocyte proliferation, apoptosis, PPARa and PPARg, and plasma insulin-like growth factor 1 (IGF-1) levels were assessed after 6 and 10 mo. Mean body and liver weights, plasma IGF-1 concentration, hepatic expressions of proliferating cellular nuclear antigen and Ki-67, and cyclin D1 in ethanol-fed rats were all significantly lower after 10 mo of treatment compared with control rats. In addition, levels of hepatic PPARg protein, not PPARa, were significantly higher in the ethanol-fed rats after prolonged treatment. Although ethanol feeding also resulted in significantly fewer altered hepatic foci, hepatocellular adenoma was detected in ethanol-fed rats at 10 mo, but not in control rats given the same dose of DEN. Together, these results indicate that chronic, excessive ethanol consumption impairs normal hepatocyte proliferation, which is associated with reduced IGF-1 levels, but promotes hepatic carcinogenesis.