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.