Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis
Open accessAbstract
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.
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Progression of chronic liver injury is associated with a relationship between dysbiosis and specific bile acid formation (DCA, LCA, TCDCA, GCDCA), with increases in Clostridium, Bacteroides, and E. coli and reduction in A. muciniphila that significantly correlated with specific increases in secondary bile acids.
“The progression of chronic liver injury was associated with a relationship between dysbiosis and specific BA formation (DCA, LCA, TCDCA, GCDCA) with an increase in specific bacteria genera (Clostridium, Bacteroides, E. Coli) and reduction in A. muciniphila that significantly correlated with specific increases in secondary BA [248,249].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [248]
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- Authors
- Xie, G., Wang, X., Huang, F., Zhao, A., Chen, W., Yan, J., Zhang, Y., Lei, S., Ge, K., Zheng, X., Liu, J., Su, M., Liu, P., & Jia, W.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
- University of Hawaii Cancer Center (US)
- Corresponding author
- Jia, Wei
- ORCID
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2016-06-17
- Volume
- 139
- Issue
- 8
- Pages
- 1764-1775
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- PMC
- PMC5493524
- OpenAlex
- W2409636417
- Cited by
- 252
- References
- 51
- Citations by year
- 2026: 17 · 2025: 31 · 2024: 32 · 2023: 27 · 2022: 32 · 2021: 34 · 2020: 30 · 2019: 17 · 2018: 18 · 2017: 13 · 2016: 1
- FWCI
- 8.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health Grant (1U01CA188387-01A1)
- the State Key Development Programs (973) of Basic Research of China (2012CB910102)
- International Science & Technology Cooperation Program of China (2014DFA31870)
- National Natural Science Foundation of China (81573873, 8153000502, 81273728)
- the Natural Science Foundation of Shanghai, China (14ZR1441400)
- the Program for Budgeted Scientific Research Project of Shanghai Municipal Education Commission, China (I3YZ044)
- E-institutes of Shanghai Municipal Education Commission, China (E03008)
- NCI (CA071789-15)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- bile acids, hepatocarcinogenesis, hepatocellular carcinoma, nonalcoholic steatohepatitis, hydrophobic bile acids, deoxycholate, taurocholate, taurochenodeoxycholic acid, taurolithocholate, gut microbiota, cholestyramine, bile acid transporters, high-fat diet, streptozotocin, C/EBPα, tumor suppressor, liver inflammation, cell proliferation
- MeSH terms
- Gastrointestinal Microbiome, Animals, Bile Acids and Salts, Cell Line, Deoxycholic Acid, Female, Humans, Liver Neoplasms, Liver Neoplasms, Experimental, Male, Mice, Inbred C57BL, Pregnancy, Streptozocin, Taurochenodeoxycholic Acid, Taurocholic Acid, Taurolithocholic Acid, Mice, Hep G2 Cells, Diet, High-Fat, Carcinogenesis, Non-alcoholic Fatty Liver Disease
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