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Disordered farnesoid <scp>X</scp> receptor signaling is associated with liver carcinogenesis in <scp> Abcb11 </scp> ‐deficient mice
- Source :
- The Journal of Pathology. 255:412-424
- Publication Year :
- 2021
- Publisher :
- Wiley, 2021.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 10969896 and 00223417
- Volume :
- 255
- Database :
- OpenAIRE
- Journal :
- The Journal of Pathology
- Accession number :
- edsair.doi.dedup.....a1c4fcbb52f47a6ae037885d1ea3d275