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.

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
  • 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
  • P-glycoprotein 2
  • Phospholipids

Grant support