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Updated: May 22, 2026
Measurement of Fatty Acid β-Oxidation in a Suspension of Freshly Isolated Mouse Hepatocytes
Published on: September 9, 2021
Abcb11 deficiency induces cholestasis coupled to impaired β-fatty acid oxidation in mice
Yuanyuan Zhang1, Fei Li, Andrew D Patterson
1Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA.
Insights
Mice lacking the bile salt export pump (BSEP) show impaired fatty acid metabolism before liver disease onset. These metabolic changes may contribute to cholestatic liver damage progression in BSEP deficiency.
Area of Science:
- Biochemistry
- Genetics
- Hepatology
Background:
- The bile salt export pump (BSEP), encoded by ABCB11, is crucial for eliminating bile salts from the liver.
- Human ABCB11 deficiency causes severe progressive cholestatic liver disease.
- Previous mouse models of Abcb11 deficiency did not fully replicate human disease phenotypes.
Purpose of the Study:
- To investigate hepatic metabolic alterations in Abcb11-deficient mice.
- To determine if these metabolic changes precede cholestasis and predict liver injury.
Main Methods:
- Generation of Abcb11 knock-out (KO) mice on a C57BL/6J background.
- Analysis of hepatic lipid metabolism and gene expression.
- Measurement of serum free-fatty acids and white adipose tissue.
- Metabolomic analysis to identify fatty acid metabolites.
Main Results:
- Abcb11 KO mice exhibit altered hepatic lipid metabolism and reduced mitochondrial fatty acid oxidation gene expression prior to cholestasis.
- Increased serum free-fatty acids, reduced white adipose tissue, and impaired long-chain fatty acid beta-oxidation were observed.
- Metabolomic analysis revealed elevated phenylpropionylglycine and phenylacetylglycine, indicating impaired mitochondrial fatty acid beta-oxidation.
Conclusions:
- Abcb11 deficiency in mice leads to significant alterations in hepatic fatty acid metabolism preceding cholestasis.
- Impaired mitochondrial fatty acid oxidation and associated metabolic changes may exacerbate cholestatic liver damage through reactive oxygen species production.
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.
