Document Detail


Abcb11 deficiency induces cholestasis coupled to impaired β-fatty acid oxidation in mice.
MedLine Citation:
PMID:  22619174     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Yuanyuan Zhang; Fei Li; Andrew D Patterson; Yao Wang; Kristopher W Krausz; Geoffrey Neale; Sarah Thomas; Deepa Nachagari; Peter Vogel; Mary Vore; Frank J Gonzalez; John D Schuetz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-22
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-07-16     Completed Date:  2012-09-26     Revised Date:  2013-07-17    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  24784-94     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA.
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MeSH Terms
Descriptor/Qualifier:
ATP-Binding Cassette Transporters / genetics,  metabolism*
Animals
Cholestasis / etiology*,  genetics,  metabolism*
Fatty Acids / metabolism*
Liver / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondria / metabolism
Oxidation-Reduction
Real-Time Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
2R01-GM60904/GM/NIGMS NIH HHS; CA21865/CA/NCI NIH HHS; P30 CA21745/CA/NCI NIH HHS; R21 HL114066/HL/NHLBI NIH HHS; R21HL114066/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Abcb11 protein, mouse; 0/Fatty Acids
Comments/Corrections

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