Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine-initiated early hepatocarcinogenesis in rats

Authors

  • Yan Wang,

    1. Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA
    2. Department of Nutritional Science, Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA
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  • Lynne M. Ausman,

    1. Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA
    2. Department of Nutritional Science, Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA
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  • Andrew S. Greenberg,

    1. Department of Nutritional Science, Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA
    2. Obesity and Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA
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  • Robert M. Russell,

    1. Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA
    2. Department of Nutritional Science, Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA
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  • Xiang-Dong Wang

    Corresponding author
    1. Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA
    2. Department of Nutritional Science, Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA
    • Nutrition and Cancer Biology Laboratory, Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA
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    • Fax: +1-617-556-3344.


  • Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of National Institute of Health and the U.S. Department of Agriculture.

Abstract

It has been suggested that patients with nonalcoholic steatohepatitis (NASH) may have high risk for liver cancer. However, it is unknown whether high-fat diet (HFD) induced NASH promotes hepatocarcinogenesis. In this study, Sprague-Dawley rats were injected with a low dose of hepatic carcinogen diethylnitrosamine (DEN) and then fed either Lieber-DeCarli control diet (CD) or HFD for 6 weeks. Liver histology and the hepatic placental form of glutathione S-transferase (P-GST) positive foci were examined. Expression levels of proliferating cell nuclear antigen (PCNA), cyclinD1, phosphorylated mitogen-activated protein kinase (MAPK) including extracellular signal-regulated kinase (ERK) and p38, as well as tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappaB (NF-κB) were measured in the liver. Induction of lipid peroxidation end products (malondialdehyde plus 4-hydroxynonenal) in liver and apoptotic hepatocytes were also assessed. Results showed that HFD-fed rats developed significantly higher incidence and multiplicity of P-GST 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-α mRNA and nuclear NF-κB p65 protein were observed in HFD group than in CD group. These data clearly demonstrate that NASH induced by HFD promoted DEN-initiated early hepatocarcinogenesis, which was associated with elevated TNF-α/NF-κB signaling and MAPK related hepatocyte proliferation. © 2008 Wiley-Liss, Inc.

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