Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2−/− mice
Date
2019
Authors
Wang, Renxue
Sheps, Jonathan A.
Liu, Lin
Han, Jun
Chen, Patrick S. K.
Lamontagne, Jason
Wilson, Peter D.
Welch, Ian
Borchers, Christoph H.
Ling, Victor
Journal Title
Journal ISSN
Volume Title
Publisher
Journal of Lipid Research
Abstract
Bile acid imbalance causes progressive familial intrahepatic cholestasis type 2 (PFIC2) or type 3 (PFIC3), severe liver diseases associated with genetic defects in the biliary bile acid transporter bile salt export pump (BSEP; ABCB11) or phosphatidylcholine transporter multidrug resistance protein 3 (MDR3; ABCB4), respectively. Mdr2−/− mice (a PFIC3 model) develop progressive cholangitis, ductular proliferation, periportal fibrosis, and hepatocellular carcinoma (HCC) because the nonmicelle-bound bile acids in the bile of these mice are toxic. We asked whether the highly hydrophilic bile acids generated by Bsep−/− mice could protect Mdr2−/− mice from progressive liver damage. We generated double-KO (DKO: Bsep−/− and Mdr2−/−) mice. Their bile acid composition resembles that of Bsep−/− mice, with increased hydrophilic muricholic acids, tetrahydroxylated bile acids (THBAs), and reduced hydrophobic cholic acid. These mice lack the liver pathology of their Mdr2−/− littermates. The livers of DKO mice have gene expression profiles very similar to Bsep−/− mice, with 4,410 of 6,134 gene expression changes associated with the Mdr2−/− mutation being suppressed. Feeding with THBAs partially alleviates liver damage in the Mdr2−/− mice. Hydrophilic changes to biliary bile acid composition, including introduction of THBA, can prevent the progressive liver pathology associated with the Mdr2−/− (PFIC3) mutation.
Description
Keywords
bile acids and salts/biosynthesis, cancer, gene expression, hepatic cellular carcinoma, hydrophobicity, inflammation, liver fibrosis, progressive familial intrahepatic cholestasis, tetrahydroxylated bile acids, UVic Genome BC Proteomics Centre
Citation
Wang, R., Sheps, J. A., Liu, L., Han, J., Chen, P. S. K., Borchers, C. H., … Ling, V. (2019). Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2−/− mice. Journal of Lipid Research, 60(1), 85-97. https://doi.org/10.1194/jlr.M088070.