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

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 BSEP (ABCB11), or phosphatidylcholine transporter MDR3 (ABCB4), respectively. Mdr2 -/- mice (a PFIC3 model) develop progressive cholangitis, ductular proliferation, periportal fibrosis, and hepatocellular carcinoma (HCC) because the non-micelle-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 knockout (DKO: Bsep -/- and Mdr2 -/- ) mice. Their bile acid composition resembles that of Bsep-/- mice, with increased hydrophilic muricholic acids, tetrahydroxylated bile acids (THBA), 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 4410 out of 6134 gene expression changes associated with the Mdr2 -/- mutation being suppressed. Feeding with THBA partially alleviates liver damage in the Mdr2 -/- mice. Conclusion: Hydrophilic changes to biliary bile acid composition, including introduction of THBA, can prevent the progressive liver pathology associated with the Mdr2 -/- (PFIC3) mutation.