Skip to main content
ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #229022
Title: Nonalcoholic Steatohepatitis Induced by a High-Fat Diet Promotes Diethylnitrosamine Initiated Early Hepatocarcinogenesis in Rats

Author
item WANG, YAN - JM USDA HNRCA @ TUFTS
item AUSMAN, LYNNE - JM USDA HNRCA @ TUFTS
item Russell, Robert
item Greenberg, Andrew
item Wang, Xiang-Dong

Submitted to: International Journal of Cancer
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/26/2008
Publication Date: 2/1/2009
Citation: Wang, Y., Ausman, L.M., Russell, R., Greenberg, A.S., Wang, X. 2009. Nonalcoholic Steatohepatitis Induced by a High-Fat Diet Promotes Diethylnitrosamine Initiated Early Hepatocarcinogenesis in Rats. International Journal of Cancer. 124: 540-546.

Interpretive Summary: It has been suggested that patients with inflammatory fatty liver called nonalcoholic steatohepatitis (NASH) have a high risk for liver cancer. In the present study, we clearly demonstrated that NASH induced by a high-fat diet in rat model could promote the development of early cancerous lesion in the liver, as compared with rats fed the control diet. The high prevalence of precancerous lesion was accompanied by increased cell growth rather than impaired cell death. The mitogen-activated protein kinase (MAPK) cascade associated with high oxidative stress and elevated TNFalpha/NF-kappaB signaling could contribute to this process.

Technical Abstract: It has been suggested that patients with nonalcoholic steatohepatitis (NASH) have a high risk for liver cancer. However, it is unknown whether high-fat diet induced NASH promotes chemical carcinogen-initiated hepatocarcinogenesis. In the present 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 high-fat diet (HFD) for six 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 MAPK including extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and p38, as well as TNF-alpha and NF-kappaB were measured in the liver. Induction of lipid peroxidation end products [malondialdehyde (MDA) plus 4-hydroxynonenal (4-HNE)] and apoptotic hepatocytes in the liver were also assessed. Results showed that HFD-fed rats developed significantly higher incidence and multiplicity of P-GST positive foci along with the significant fat accumulation, infiltration of inflammatory cells and higher lipid peroxidation in the liver, as compared with rats fed the CD. This high prevalence of preneoplasm in the liver was accompanied by greater PCNA expression and cyclinD1 protein concentration but little change in hepatocyte apoptosis. HFD feeding significantly elevated hepatic phosphorylated ERK but reduced phosphorylated p38 without influencing JNK activation as compared with the CD feeding. In addition, a significantly higher expression of TNF-alpha mRNA and nuclear NF-kappaB p65 protein were observed in DEN+HFD group than those in DEN+CD group. These data clearly demonstrate that NASH induced by high-fat diet promoted DEN-initiated early hepatocarcinogenesis, which was associated with elevated TNFalpha/NF-kappaB signaling and MAPK related hepatocyte proliferation.