Effects of lycopene vs. tomato extract on early hepatocarcinogenesis in high-fat diet induced nonalcoholic steatohepatitis (NASH).

摘要

The first part of this research was to examine whether nonalcoholic steatohepatitis (NASH) could promote the development of preneoplastic lesions in the liver using animal models. Two studies were carried out: firstly, feeding of Lieber-DeCarli high-fat diet to Sprague-Dawley rats for 6-weeks caused significantly increased fat accumulation and hepatic inflammatory cells in the liver, which was associated with higher lipid peroxidation, CYP2E1 protein and TNFalpha mRNA expression as well as cellular apoptosis as compared with those in control diet group; secondly, a low dose of diethylnitrosamine carcinogen was administered to rats for tumor initiation and then followed by feeding of the same high-fat and control diets for 6 weeks. The multiplicity of altered hepatic foci were significantly greater in the high-fat diet-induced NASH group relative to control group. The induction of foci growth mainly resulted from upregulated cell proliferation rather than impaired cell apoptosis. The increased activation or Erk and NF-kappaB in response to high oxidative stress and inflammation could contribute to this preneoplastic process. The second part of this research was to determine whether lycopene and tomato extract could both inhibit the incidence and/or multiplicity of altered hepatic foci promoted by NASH through inhibiting cell proliferation and/or inducing cell apoptosis and whether the protective efficacy of tomato extract could be better than that of lycopene. Purified lycopene compound and tomato extract, which contain equivalent amount of lycopene, were applied to the above animal model for 6 weeks. The physiologically relevant concentrations of lycopene were achieved in both plasma and liver and were similar between tomato extract and lycopene supplemental groups in either diet. The multiplicity of the altered hepatic foci and cell proliferation as well as Erk and NF-kappaB activation were equally inhibited by both dietary supplements. The antioxidant efficacy manifested by lower lipid peroxidation from both supplements was mainly responsible for this benefit, although different mechanisms (e.g., lower CYP2E1 by tomato extract but higher nuclear Nrf2 and HO-1 by lycopene treatment) might be involved. Tomato extracts also exhibited an additional anti-inflammatory effect in this model. Our study clearly demonstrated that high fat diet induced NASH promotes the development of preneoplastic foci in the liver and dietary supplementations of lycopene and tomato extract could equally inhibit foci growth through overlapping mechanisms. (Abstract shortened by UMI.)