Arylamine N-acetyltransferase 2 (NAT2) exhibits a well-characterized genetic polymorphism in humans that influences the metabolism of drugs and xenobiotics. Recent research, including genome-wide association studies, has linked NAT2 genetic variants to varying risks of dyslipidemia and cardiometabolic disorders, indicating a potential previously unrecognized role for NAT2 in metabolic disease pathophysiology. Consistent with this, our recent work demonstrated that human NAT2 expression is differentially modulated by glucose and insulin. Furthermore, in silico analyses revealed that NAT2 is co-expressed with liver-enriched nuclear receptors, such as NR1H4 (FXR) and NR1I2 (PXR), which are known to regulate hepatic glucose and lipid metabolism. Identifying the transcriptional regulators of NAT2 could provide insights into novel hepatic functions of this enzyme. Therefore, the current study was undertaken to examine whether hepatic nuclear receptors transcriptionally regulate NAT2. To investigate this, cryopreserved human hepatocytes were exposed to agonists targeting four distinct hepatic transcription factors/nuclear receptors—FXR (NR1H4), PXR (NR1I2), LXR (NR1H3), and PPARα (PPARA)—and the resulting changes in NAT2 mRNA levels were assessed. Although treatment with FXR, PXR, or LXR agonists (GW-4064, SR-12813, or GW-3965) effectively upregulated their respective target genes, these agonists did not produce a significant change in NAT2 transcript levels in human hepatocytes. Treatment with the PPARα agonist GW-7647 led to a statistically significant reduction in NAT2 mRNA, but the effect was minimal. In conclusion, the nuclear receptors assessed in this work—FXR, PXR, LXR, and PPARα—did not meaningfully influence NAT2 gene expression in cryopreserved human hepatocytes. Further investigations are necessary to determine which transcriptional factors control NAT2 expression in the liver.
