Arylamine N-acetyltransferase 2 (NAT2) is well-known for its role in phase II metabolism of xenobiotics and drugs. More recently, genome wide association studies and murine models implicated NAT2 in regulation of insulin sensitivity and plasma lipid levels. However, the mechanism remains unknown. Transcript levels of human NAT2 varied dynamically in HepG2 (hepatocellular) cells, depending on the nutrient status of the culture media. Culturing the cells in the presence of glucose induced NAT2 mRNA expression as well as its N-acetyltransferase activity significantly. In addition, insulin or acetate treatment also significantly induced NAT2 mRNA. We examined and compared the glucose- and acetate-dependent changes in NAT2 expression to those of genes involved in glucose and lipid metabolism, including FABP1, CPT1A, ACACA, SCD, CD36, FASN, ACLY, G6PC, and PCK1. Genes that are involved in fatty acid transport and lipogenesis, such as FABP1 and CD36, shared a similar pattern of expression with NAT2. In silico analysis of genes co-expressed with NAT2 revealed an enrichment of biological processes involved in lipid and cholesterol biosynthesis and transport. Among these, A1CF (APOBEC1 complementation factor) showed the highest correlation with NAT2 in terms of its expression in normal human tissues. The current study shows, for the first time, that human NAT2 is transcriptionally regulated by glucose and insulin in liver cancer cell lines and that the gene expression pattern of NAT2 is similar to that of genes involved in lipid metabolism and transport.
Arylamine N-acetyltransferase 2 (NAT2) is a phase II metabolic enzyme, best known for metabolism of aromatic amines and hydrazines. Genetic variants occurring in the NAT2 coding region have been well-defined and are known to affect the enzyme activity or protein stability. Individuals can be categorized into rapid, intermediate, and slow acetylator phenotypes that significantly alter their ability to metabolize arylamines, including drugs (e.g., isoniazid) and carcinogens (e.g., 4-aminobiphenyl). However, functional studies on non-coding or intergenic variants of NAT2 are lacking. Multiple, independent genome wide association studies (GWAS) have reported that non-coding or intergenic variants of NAT2 are associated with elevated plasma lipid and cholesterol levels, as well as cardiometabolic disorders, suggesting a novel cellular role of NAT2 in lipid and cholesterol homeostasis. The current review highlights and summarizes GWAS reports that are relevant to this association. We also present a new finding that seven, non-coding, intergenic NAT2 variants (i.e., rs4921913, rs4921914, rs4921915, rs146812806, rs35246381, rs35570672, and rs1495741), which have been associated with plasma lipid and cholesterol levels, are in linkage disequilibrium with one another, and thus form a novel haplotype. The dyslipidemia risk alleles of non-coding NAT2 variants are associated with rapid NAT2 acetylator phenotype, suggesting that differential systemic NAT2 activity might be a risk factor for developing dyslipidemia. The current review also discusses the findings of recent reports that are supportive of the role of NAT2 in lipid or cholesterol synthesis and transport. In summary, we review data suggesting that human NAT2 is a novel genetic factor that influences plasma lipid and cholesterol levels and alters the risk of cardiometabolic disorders. The proposed novel role of NAT2 merits further investigations.
Humans are exposed to heterocyclic amine (HCA) mutagens produced in meats cooked at high temperatures or until well‐done. A recent epidemiological study documented associations of high HCA intake with increased prevalence of insulin resistance, which is one of the hallmarks of type II diabetes mellitus and metabolic syndrome. However, it is unknown if HCAs directly induce insulin resistance. To investigate the effects of HCA exposure on insulin sensitivity, we subjected HepG2 (hepatocellular carcinoma) cells and primary human hepatocytes to 2‐amino‐3,4‐dimethylimidazo[4,5‐f]quinoline (MeIQ) and measured changes in insulin signaling, gluconeogenic gene expression, and glucose production. HepG2 cells were treated with varying concentrations of MeIQ (0‐100 μM), then treated with insulin and analyzed for changes in insulin signaling via p‐AKT induction on Western blot. MeIQ exposure decreased insulin‐induced p‐AKT levels in low glucose conditions, suggesting that the cells become insulin resistant in the presence of MeIQ. Additionally, the MeIQ treatment significantly upregulated the transcripts of genes involved in gluconeogenesis (e.g., G6PC and PCK1) in HepG2 cells. Similarly, primary human hepatocytes exposed to MeIQ also showed significant increases in gluconeogenic genes, compared to the vehicle treated cells. These results suggest that MeIQ impairs insulin signaling and potentially induces glucose production in hepatocytes. We then tested if the gene expression changes induced by MeIQ leads to increases in glucose production in primary hepatocytes. Despite upregulation of gluconeogenic genes, there were no significant changes in glucose production between control and MeIQ‐treated cells. Future studies will examine whether MeIQ exposure alters the suppressive effects of insulin on gluconeogenic gene expression and glucose production and test additional HCAs. The alterations in insulin signaling and gluconeogenic gene expression following MeIQ exposure in hepatocytes indicate that MeIQ may directly alter insulin sensitivity.
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