Nonalcoholic steatohepatitis induced by a high-fat diet promotes diethylnitrosamine-initiated early hepatocarcinogenesis in rats.
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-alpha), and nuclear factor-kappaB (NF-kappaB) 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-alpha mRNA and nuclear NF-kappaB 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-alpha/NF-kappaB signaling and MAPK related hepatocyte proliferation.
Wang
Yan
Y
Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
Ausman
Lynne M
LM
Greenberg
Andrew S
AS
Russell
Robert M
RM
Wang
Xiang-Dong
XD
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D004032:Diet; D004041:Dietary Fats / Q000009:adverse effects*; D004052:Diethylnitrosamine / Q000633:toxicity; D005234:Fatty Liver / Q000150:complications*; D051549:Glutathione S-Transferase pi / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002273:Carcinogens; D004041:Dietary Fats; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D004052:Diethylnitrosamine; D051549:Glutathione S-Transferase pi; C496558:Gstp1 protein, rat; D020928:Mitogen-Activated Protein Kinases