Disordered farnesoid X receptor signaling is associated with liver carcinogenesis in Abcb11 ‐deficient mice
| Autor: | Linlin Lu, Zhongqiu Liu, Xiaoyan Li, Liping Wang, Sijing Zeng, Yanmei Lou, Ming Hu, Qing Luo |
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| Rok vydání: | 2021 |
| Předmět: |
Liver tumor
Carcinogenesis medicine.drug_class Down-Regulation Receptors Cytoplasmic and Nuclear Chenodeoxycholic Acid Pathology and Forensic Medicine Bile Acids and Salts Mice chemistry.chemical_compound medicine Animals Humans ABCB11 ATP Binding Cassette Transporter Subfamily B Member 11 Liver injury Bile acid business.industry Liver Neoplasms Obeticholic acid medicine.disease Mice Inbred C57BL chemistry Hepatocellular carcinoma Cancer research Farnesoid X receptor business Liver cancer Signal Transduction |
| Zdroj: | The Journal of Pathology. 255:412-424 |
| ISSN: | 1096-9896 0022-3417 |
| DOI: | 10.1002/path.5780 |
| Popis: | ABCB11 encodes the bile salt export pump (BSEP), a key regulator in maintaining bile acid (BA) homeostasis. Although inherited ABCB11 mutations have previously been linked to primary liver cancer, whether ABCB11 deficiency leads to liver cancer remains unknown. Here, we analyzed ABCB11 mRNA expression levels in liver tumor specimens [29 with hepatocellular carcinoma (HCC), one with intrahepatic cholangiocarcinoma (ICC), and one with mixed HCC/ICC] with adjacent normal specimens and published human datasets. Liver tissues obtained from Abcb11-deficient (Abcb11-/- ) mice and wild-type mice at different ages were compared by histologic, RNA-sequencing, and BA analyses. ABCB11 was significantly downregulated in human liver tumors compared with normal controls. Abcb11-/- mice demonstrated progressive intrahepatic cholestasis and liver fibrosis, and spontaneously developed HCC and ICC over 12 months of age. Abcb11 deficiency increased BAs in the liver and serum in mice, most of which are farnesoid X receptor (FXR) antagonists/non-agonists. Accordingly, the hepatic expression and transcriptional activity of FXR were downregulated in Abcb11-/- mouse livers. Administration of the FXR agonist obeticholic acid reduced liver injury and tumor incidence in Abcb11-/- mice. In conclusion, ABCB11 is aberrantly downregulated and plays a vital role in liver carcinogenesis. The cholestatic liver injury and liver tumors developed in Abcb11-/- mice are associated with increased FXR antagonist BAs and thereby decreased activation of FXR. FXR activation might be a therapeutic strategy in ABCB11 deficiency diseases. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
| Databáze: | OpenAIRE |
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