Role of lipid and oxidative stress on carcinogenesis in the digestive system

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Non-alcoholic steatohepatitis (NASH) is a progressive liver disease followed by liver cirrhosis and even hepatocellular carcinoma. There has been no definitive treatment regimen for NASH. Hepatocyte-specific Pten deficient (Pten KO) mice possess almost the same hepatic lesions histologically as human NASH and are thought to represent some limited NASH patients. We first analyzed a comprehensive gene expression of hepatocytes derived from 10 to 35-week-old Pten KO mice using the DNA microarray technology to find out the candidate gene related to development and aggravation of human NASH. Spp1, Vnn1, Itga6. Abed2, Auh, Acox1, Pdk4, Cpt1a, Len2, Tgfbp2, Gstm6, Socs3. Tgm2, and Aldh9al were regarded as the candidate genes related to inflammation. The candidate genes of fibrosis were Sppl, Ctgf, and Cyp2c39 and moreover Cidec and Sppl were regarded as the candidate genes of carcinogenesis. To confirm that these genes contribute to the etiology of some human NASH, further investigations using human liver samples are needed. In the present study we further investigated the experimental therapeutics of NASH using a variety of antioxidants especially focusing on chemoprevention of hepatocellular carcinoma. Our study demonstrated that N-acetylcysteine diminished inflammatory changes but not steatosis per se. Therefore, we propose that a combination regimen using several antioxidants may be optimal for preventing disease progression and subsequent carcinogenesis in NASH.