title: Abcb11 deficiency induces cholestasis coupled to impaired β-fatty acid oxidation in mice.
abstract: The bile salt export pump (BSEP) is an ATP-binding cassette transporter that serves as the primary system for removing bile salts from the liver. In humans, deficiency of BSEP, which is encoded by the ABCB11 gene, causes severe progressive cholestatic liver disease from early infancy. In previous studies of Abcb11 deficiency in mice generated on a mixed genetic background, the animals did not recapitulate the human disease. We reasoned that ABCB11 deficiency may cause unique changes in hepatic metabolism that are predictive of liver injury. To test this possibility, we first determined that Abcb11 knock-out (KO) C57BL/6J mice recapitulate human deficiency. Before the onset of cholestasis, Abcb11 KO mice have altered hepatic lipid metabolism coupled with reduced expression of genes important in mitochondrial fatty acid oxidation. This was associated with increased serum free-fatty acids, reduced total white adipose, and marked impairment of long-chain fatty acid β-oxidation. Importantly, metabolomic analysis confirmed that Abcb11 KO mice have impaired mitochondrial fatty acid β-oxidation with the elevated fatty acid metabolites phenylpropionylglycine and phenylacetylglycine. These metabolic changes precede cholestasis but may be of relevance to cholestatic disease progression because altered fatty acid metabolism can enhance reactive oxygen species that might exacerbate cholestatic liver damage.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Patterson
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.forename: Sarah
authors.initials: S
authors.lastname: Thomas
authors.forename: Deepa
authors.initials: D
authors.lastname: Nachagari
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.forename: Mary
authors.initials: M
authors.lastname: Vore
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002779:Cholestasis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D005227:Fatty Acids