Abcb11 deficiency induces cholestasis coupled to impaired β-fatty acid oxidation in mice

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

Research output: Contribution to journalArticle

34 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)24784-24794
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number29
DOIs
StatePublished - Jul 13 2012

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Zhang, Y., Li, F., Patterson, A. D., Wang, Y., Krausz, K. W., Neale, G., Thomas, S., Nachagari, D., Vogel, P., Vore, M., Gonzalez, F. J., & Schuetz, J. D. (2012). Abcb11 deficiency induces cholestasis coupled to impaired β-fatty acid oxidation in mice. Journal of Biological Chemistry, 287(29), 24784-24794. https://doi.org/10.1074/jbc.M111.329318