{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T08:47:23Z","timestamp":1791103643172,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2008,9,15]],"date-time":"2008-09-15T00:00:00Z","timestamp":1221436800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2009,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>It has been suggested that patients with nonalcoholic steatohepatitis (NASH) may have high risk for liver cancer. However, it is unknown whether high\u2010fat diet (HFD) induced NASH promotes hepatocarcinogenesis. In this study, Sprague\u2010Dawley rats were injected with a low dose of hepatic carcinogen diethylnitrosamine (DEN) and then fed either Lieber\u2010DeCarli control diet (CD) or HFD for 6 weeks. Liver histology and the hepatic placental form of glutathione S\u2010transferase (P\u2010GST) positive foci were examined. Expression levels of proliferating cell nuclear antigen (PCNA), cyclinD1, phosphorylated mitogen\u2010activated protein kinase (MAPK) including extracellular signal\u2010regulated kinase (ERK) and p38, as well as tumor necrosis factor\u2010alpha (TNF\u2010\u03b1), and nuclear factor\u2010kappaB (NF\u2010\u03baB) were measured in the liver. Induction of lipid peroxidation end products (malondialdehyde plus 4\u2010hydroxynonenal) in liver and apoptotic hepatocytes were also assessed. Results showed that HFD\u2010fed rats developed significantly higher incidence and multiplicity of P\u2010GST positive foci along with more fat accumulation, infiltration of inflammatory cells and higher lipid peroxidation in the liver, when compared with rats fed the CD. This high prevalence of hepatic lesions in the liver was accompanied by greater PCNA expression and cyclinD1 protein concentration but little change in hepatocyte apoptosis. HFD feeding elevated hepatic phosphorylated ERK but reduced phosphorylated p38 when compared with the CD feeding. In addition, a significantly higher expression of TNF\u2010\u03b1 mRNA and nuclear NF\u2010\u03baB p65 protein were observed in HFD group than in CD group. These data clearly demonstrate that NASH induced by HFD promoted DEN\u2010initiated early hepatocarcinogenesis, which was associated with elevated TNF\u2010\u03b1\/NF\u2010\u03baB signaling and MAPK related hepatocyte proliferation. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.23995","type":"journal-article","created":{"date-parts":[[2008,9,15]],"date-time":"2008-09-15T19:18:32Z","timestamp":1221506312000},"page":"540-546","source":"Crossref","is-referenced-by-count":68,"title":["Nonalcoholic steatohepatitis induced by a high\u2010fat diet promotes diethylnitrosamine\u2010initiated early hepatocarcinogenesis in rats"],"prefix":"10.1002","volume":"124","author":[{"given":"Yan","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynne M.","family":"Ausman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew 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