Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2−/− mice

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dc.contributor.authorWang, Renxue
dc.contributor.authorSheps, Jonathan A.
dc.contributor.authorLiu, Lin
dc.contributor.authorHan, Jun
dc.contributor.authorChen, Patrick S. K.
dc.contributor.authorLamontagne, Jason
dc.contributor.authorWilson, Peter D.
dc.contributor.authorWelch, Ian
dc.contributor.authorBorchers, Christoph H.
dc.contributor.authorLing, Victor
dc.date.accessioned2021-01-29T19:07:57Z
dc.date.available2021-01-29T19:07:57Z
dc.date.copyright2019en_US
dc.date.issued2019
dc.description.abstractBile 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.en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.identifier.citationWang, 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.en_US
dc.identifier.urihttps://doi.org/10.1194/jlr.M088070
dc.identifier.urihttp://hdl.handle.net/1828/12624
dc.language.isoenen_US
dc.publisherJournal of Lipid Researchen_US
dc.subjectbile acids and salts/biosynthesis
dc.subjectcancer
dc.subjectgene expression
dc.subjecthepatic cellular carcinoma
dc.subjecthydrophobicity
dc.subjectinflammation
dc.subjectliver fibrosis
dc.subjectprogressive familial intrahepatic cholestasis
dc.subjecttetrahydroxylated bile acids
dc.subjectUVic Genome BC Proteomics Centre
dc.subject.departmentDepartment of Biochemistry and Microbiology
dc.titleHydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2−/− miceen_US
dc.typeArticleen_US

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