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

Renxue Wang; Jonathan A Sheps; Lin Liu; Jun Han; Patrick S K Chen; Jason Lamontagne; Peter D Wilson; Ian Welch; Christoph H Borchers; Victor Ling

doi:10.1194/jlr.M088070

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

J Lipid Res. 2019 Jan;60(1):85-97. doi: 10.1194/jlr.M088070. Epub 2018 Nov 11.

Authors

Renxue Wang¹, Jonathan A Sheps¹, Lin Liu¹, Jun Han², Patrick S K Chen³, Jason Lamontagne³, Peter D Wilson³, Ian Welch^{4

5}, Christoph H Borchers^{2

6

7}, Victor Ling^{8

4}

Affiliations

¹ BC Cancer Research Centre, Vancouver, British Columbia, Canada.
² University of Victoria-Genome BC Proteomics Centre University of Victoria, Victoria, British Columbia, Canada.
³ Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
⁴ Department of Pathology University of British Columbia, Vancouver, British Columbia, Canada.
⁵ Centre for Comparative Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
⁶ Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
⁷ Proteomics Centre, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
⁸ BC Cancer Research Centre, Vancouver, British Columbia, Canada vling@bccrc.ca.

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.

Keywords: bile acids and salts/biosynthesis; cancer; gene expression; hepatic cellular carcinoma; hydrophobicity; inflammation; liver fibrosis; progressive familial intrahepatic cholestasis; tetrahydroxylated bile acids.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / deficiency*
ATP Binding Cassette Transporter, Subfamily B / genetics
ATP Binding Cassette Transporter, Subfamily B, Member 11 / deficiency
ATP Binding Cassette Transporter, Subfamily B, Member 11 / genetics
ATP-Binding Cassette Sub-Family B Member 4
Animals
Bile Acids and Salts / chemistry
Bile Acids and Salts / pharmacology*
Biliary Tract / drug effects
Biliary Tract / metabolism*
Cytoprotection / drug effects*
Gene Knockout Techniques
Hydrophobic and Hydrophilic Interactions*
Hydroxylation
Liver / cytology
Liver / drug effects
Liver / injuries*
Liver / metabolism
Male
Mice
Mutation
Phospholipids / metabolism*

Substances

ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 11
Bile Acids and Salts
Phospholipids

Grants and funding

CIHR/Canada