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Green Tea Extract Protects Against Diethylnitrosamine‐Mediated Liver Injury And Cell Proliferation By Attenuating STAT3 And iNOS Expression In High Fat‐Induced Obese Mice With Nonalcoholic Steatohepatitis

Nonalcoholic steatohepatitis (NASH) increases hepatocellular carcinoma (HCC) risk by increasing inflammation and oncogenesis. Antiinflammatory activities of green tea extract (GTE) protect against dietary high‐fat (HF)‐induced NASH. We hypothesized that the hepatoprotective antiinflammatory activities of GTE during NASH would also prevent diethylnitrosamine (DEN)‐induced progression towards HCC. Male C57BL/6J mice (4 wk old) were fed a HF diet devoid of, or supplemented with, GTE at 2% (w/w) and received once weekly intraperitoneal injections of saline vehicle or DEN (60 mg/kg; wk 5 and 7) until 25 wk old prior to assessing NASH, inflammation, and oncogenic responses. DEN did not (P>0.05) exacerbate liver steatosis, hepatocyte ballooning, or mRNA expression of TNFα and MCP‐1 compared with saline‐treated mice. However, GTE protected against (P<0.05) histologic evidence of NASH and TNFα and MCP‐1 expression to a similar extent in saline‐ and DEN‐injected controls. GTE inhibited DEN‐induced increases in serum alanine aminotransferase (ALT) activity and iNOS mRNA expression, which were not different from the lowered levels observed in saline‐treated mice fed GTE. GTE also similarly inhibited DEN‐induced increases in signal transducer and activator of transcription 3 (STAT3) protein expression to levels not different from those lowered by GTE in saline‐treated mice. GTE attenuated positive staining towards hepatocyte proliferating cell nuclear antigen (PCNA) that was otherwise exacerbated by DEN. Serum ALT was correlated (r = 0.74–0.83; P<0.0001) with iNOS, STAT3, and PCNA. Likewise, iNOS correlated with both PCNA and STAT3 (r = 0.64–0.65; P<0.05), suggesting that iNOS‐induced inflammation centrally regulates liver injury and oncogenic cell proliferation. GTE protects against DEN‐exacerbated STAT3/iNOS‐mediated oncogenic responses that otherwise provoke liver injury and cell proliferation.