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Evaluation of Farnesoid X Receptor Target Gene Induction in Human Hepatocytes: Amino Acid Conjugation

[ Vol. 11 , Issue. 2 ]

Author(s):

Jean Simmermacher* and Michael Sinz   Pages 138 - 143 ( 6 )

Abstract:


Background: The nuclear hormone receptor, Farnesoid X Receptor (FXR) regulates the transcription of genes associated with bile acid metabolism and disposition.

Objective: This study investigates possible changes in the expression of target genes responsible for amino acid conjugation, i.e., Bile Acid-CoA Synthetase (BACS) and bile acid-CoA: amino acid Nacetyltransferase (BAT). These genes have been shown to be inducible by FXR agonists in rat models, however, to date no studies have been conducted in a human hepatocyte model.

Results: In human hepatocytes, treatment with the FXR agonists GW4064 (1.0 µM) and WAY362450 (0.1 µM) did not significantly induce the mRNA expression of BACS and BAT genes. However, other target genes associated with FXR activation, such as Bile Salt Export Pump (BSEP), Short Heterodimer Partner (SHP), Multidrug Resistance-associated Protein 2 (MRP2) and Multidrug Resistance Protein 3 (MDR3), were upregulated. Interestingly, a follow up study conducted in rat hepatocytes indicated that GW4064 induced the BACS gene while WAY362450 induced the BAT gene, confirming literature results that these genes can be induced in rat.

Conclusion: In conclusion, there appears to be some species differences in the activation of FXR target genes.

Keywords:

Farnesoid X receptor, bile acid, amino acid conjugation, enzyme induction, metabolism, hepatocytes.

Affiliation:

Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492

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