Dysregulated bile acids (BAs) are closely associated with liver diseases and attributed to altered gut microbiota. Here, we show that the intrahepatic retention of hydrophobic BAs including deoxycholate (DCA), taurocholate (TCA), taurochenodeoxycholate (TCDCA), and taurolithocholate (TLCA) were substantially increased in a streptozotocin and high fat diet (HFD) induced nonalcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) mouse model. Additionally chronic HFD-fed mice spontaneously developed liver tumors with significantly increased hepatic BA levels. Enhancing intestinal excretion of hydrophobic BAs in the NASH-HCC model mice by a 2% cholestyramine feeding significantly prevented HCC development. The gut microbiota alterations were closely correlated with altered BA levels in liver and feces. HFD-induced inflammation inhibited key BA transporters, resulting in sustained increases in intrahepatic BA concentrations. Our study also showed a significantly increased cell proliferation in BA treated normal human hepatic cell lines and a down-regulated expression of tumor suppressor gene CEBPa in TCDCA treated HepG2 cell line, suggesting that several hydrophobic BAs may collaboratively promote liver carcinogenesis.
[1]Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Key Lab Diabet Mellitus, Shanghai, Peoples R China.
[2]Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Ctr Translat Med, Shanghai, Peoples R China.
[3]Univ Hawaii, Ctr Canc, Metabol Shared Resource, Honolulu, HI 96822 USA.
[4]Shanghai Univ Tradit Chinese Med, E Inst Shanghai Municipal Educ Comm, Shanghai, Peoples R China.
[5]Shanghai Univ Tradit Chinese Med, Inst Liver Dis, Shuguang Hosp, Key Lab Liver & Kidney Dis,Minist Educ, Shanghai, Peoples R China.
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