Green tea extract inhibits early oncogenic responses in mice with nonalcoholic steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH) increases hepatocellular carcinoma (HCC) risk. We hypothesized that the hepatoprotective anti-inflammatory benefits of catechin-rich green tea extract (GTE) would protect against HCC progression by inhibiting NASH-associated liver injury and pro-oncogenic responses. We used an HCC model in high-fat (HF)-fed mice that mimics early oncogenic events during NASH without inducing tumorigenesis and premature mortality. Male C57BL/6J mice (4-weeks old) were fed a HF diet containing GTE at 0% or 2%. Mice were administered saline or diethylnitrosamine (DEN; 60 mg kg⁻¹, i.p.) at 5-weeks and 7-weeks of age. NASH, inflammation, fibrosis, and oncogenic responses were assessed at 25-weeks of age. Saline-treated mice showed prominent histopathological signs of steatosis and hepatocellular ballooning. Although DEN did not impact adiposity, steatosis, ballooning and hepatic lipid accumulation, these parameters were attenuated by GTE regardless of DEN. Hepatic lipid peroxidation and fibrosis that were increased by DEN were attenuated by GTE. Hepatic TLR4, MCP1 and TNFα mRNA levels were unaffected by DEN, whereas iNOS was increased by DEN. These transcripts were lowered by GTE. GTE attenuated the frequency of PCNA+ hepatocytes and mRNA expression of cyclin D1, MIB1 and Ki-67 that were otherwise increased by DEN. GTE increase APAF1 mRNA that was otherwise lowered by DEN. Relative to saline-treated mice, DEN increased mRNA levels of oncostatin M, gp130, c-Fos, c-Myc and survivin; each was lowered by GTE in DEN-treated mice. These findings indicate that GTE may protect against hepatic oncogenesis by limiting early steps in the carcinogenic cascade related to NASH-associated HCC.