| First Author | Wang R | Year | 2019 |
| Journal | J Lipid Res | Volume | 60 |
| Issue | 1 | Pages | 85-97 |
| PubMed ID | 30416103 | Mgi Jnum | J:269096 |
| Mgi Id | MGI:6272936 | Doi | 10.1194/jlr.M088070 |
| Citation | Wang R, et al. (2019) Hydrophilic bile acids prevent liver damage caused by lack of biliary phospholipid in Mdr2(-/-) mice. J Lipid Res 60(1):85-97 |
| abstractText | 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. |
