Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis.

Abstract

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 CEBPα in TCDCA treated HepG2 cell line, suggesting that several hydrophobic BAs may collaboratively promote liver carcinogenesis.

• Authors: Guoxiang Xie, Xiaoning Wang, Fengjie Huang, Aihua Zhao, Wenlian Chen, Jingyu Yan, Yunjing Zhang, Sha Lei, Kun Ge, Xiaojiao Zheng, Jiajian Liu, Mingming Su, Ping Liu, Wei Jia
• Journal: International journal of cancer (Int J Cancer) Vol. 139 Issue 8 Pg. 1764-75 (10 15 2016) ISSN: 1097-0215 [Electronic] United States
• PMID: 27273788 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2016 UICC.

Chemical References

• Bile Acids and Salts
• Deoxycholic Acid
• Taurochenodeoxycholic Acid
• Taurolithocholic Acid
• Taurocholic Acid
• Streptozocin

Topics

• Animals
• Bile Acids and Salts (metabolism)
• Carcinogenesis (metabolism, pathology)
• Cell Line
• Deoxycholic Acid (metabolism)
• Diet, High-Fat
• Female
• Gastrointestinal Microbiome
• Hep G2 Cells
• Humans
• Liver Neoplasms (etiology, metabolism, microbiology, pathology)
• Liver Neoplasms, Experimental (etiology, metabolism, microbiology, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (etiology, metabolism, microbiology, pathology)
• Pregnancy
• Streptozocin
• Taurochenodeoxycholic Acid (metabolism)
• Taurocholic Acid (metabolism)
• Taurolithocholic Acid (metabolism)