Investigation on regulation of -acetyltransferase 2 expression by nuclear receptors in human hepatocytes.

INTRODUCTION

Arylamine -acetyltransferase 2 (NAT2) expresses a well-defined genetic polymorphism in humans that modifies drug and xenobiotic metabolism. Recent studies and genome wide association studies have reported that genetic variants of are associated with differential risks of developing dyslipidemia and cardiometabolic disorders, suggesting a previously unrecognized role of NAT2 in pathophysiology of metabolic disorders. In support of this notion, we recently showed that human expression is differentially regulated by glucose and insulin. Moreover, our analysis showed that is co-expressed with nuclear receptors enriched in the liver, e.g., (FXR) and (PXR), that have been previously implicated in regulation of hepatic glucose and lipid homeostasis. Identification of transcriptional regulator(s) of human would aid in understanding novel functions that it may play in the liver. Thus, the present study was designed to investigate if is transcriptionally regulated by hepatic nuclear receptors.

METHODS

To test this, we treated cryopreserved human hepatocytes with agonists towards four different hepatic transcription factors/nuclear hormone receptors, namely FXR (NR1H4), PXR (NR1I2), LXR (NR1H3), and PPARα (PPARA), and measured their effects on the level of mRNA.

RESULTS

While the treatment with a FXR, PXR, or LXR agonist (i.e., GW-4064, SR-12813, or GW-3965) significantly induced their respective target genes, treatment with these agonists did not significantly alter the transcript level of in human hepatocytes. PPARα agonist, GW-7647, treatment resulted in a statistically significant decrease in the transcript level. However, its magnitude was marginal.

CONCLUSION

In summary, hepatic nuclear receptors we examined in the present study (FXR, PXR, LXR, and PPARα) did not significantly alter expression in cryopreserved human hepatocytes. Additional studies are needed to identify transcriptional regulators of hepatic NAT2 expression.