AUTHOR=Hong Kyung U. , Aureliano Anthony P. , Walls Kennedy M. , Hein David W. 

TITLE=Investigation on regulation of N-acetyltransferase 2 expression by nuclear receptors in human hepatocytes

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1488367

DOI=10.3389/fphar.2024.1488367

ISSN=1663-9812

ABSTRACT=<sec><title>Introduction</title><p>Arylamine <italic>N</italic>-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 <italic>NAT2</italic> 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 <italic>NAT2</italic> expression is differentially regulated by glucose and insulin. Moreover, our <italic>in silico</italic> analysis showed that <italic>NAT2</italic> is co-expressed with nuclear receptors enriched in the liver, e.g., <italic>NR1H4</italic> (FXR) and <italic>NR1I2</italic> (PXR), that have been previously implicated in regulation of hepatic glucose and lipid homeostasis. Identification of transcriptional regulator(s) of human <italic>NAT2</italic> would aid in understanding novel functions that it may play in the liver. Thus, the present study was designed to investigate if <italic>NAT2</italic> is transcriptionally regulated by hepatic nuclear receptors.</p></sec><sec><title>Methods</title><p>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 <italic>NAT2</italic> mRNA.</p></sec><sec><title>Results</title><p>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 <italic>NAT2</italic> in human hepatocytes. PPARα agonist, GW-7647, treatment resulted in a statistically significant decrease in the <italic>NAT2</italic> transcript level. However, its magnitude was marginal.</p></sec><sec><title>Conclusion</title><p>In summary, hepatic nuclear receptors we examined in the present study (FXR, PXR, LXR, and PPARα) did not significantly alter <italic>NAT2</italic> expression in cryopreserved human hepatocytes. Additional studies are needed to identify transcriptional regulators of hepatic NAT2 expression.</p></sec>