Acetylator Genotype-Dependent Dyslipidemia in Rats Congenic for N-Acetyltransferase 2

Hong, Kyung U.; Doll, Mark A.; Lykoudi, Angeliki; Salazar‐González, Raúl A.; Habil, Mariam R.; Walls, Kennedy M; Bakr, Alaa F.; Ghare, Smita; Barve, Shirish; Arteel, Gavin E.; Hein, David W.

doi:10.1016/j.toxrep.2020.09.011

Cited by 7 publications

(4 citation statements)

References 62 publications

(80 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In rats, Nat2 acetylator status has been shown to influence plasma lipid and cholesterol levels. In our previous study ( Hong et al, 2020 ), we investigated the interaction between diet (control vs. high-fat) and acetylator phenotype (rapid vs. slow) using previously established congenic rat lines that exhibit rapid or slow NAT2 acetylator phenotypes. Male and female rats of each genotype were fed control or high-fat diet for 26 weeks.…”

Section: Evidence Supporting the Role Of Nat2 In Lipid And Cholestero...mentioning

confidence: 99%

“…Regardless of the diet, rapid acetylator rats (with higher NAT2 activity) were more prone to develop dyslipidemia overall. Rapid rats exhibited higher plasma levels of triglyceride and LDL, and lower HDL level, compared to slow acetylator rats ( Hong et al, 2020 ). Rapid acetylator rats also displayed a significantly higher total cholesterol-to-HDL ratio ( Hong et al, 2020 ).…”

Section: Evidence Supporting the Role Of Nat2 In Lipid And Cholestero...mentioning

confidence: 99%

“…Rapid rats exhibited higher plasma levels of triglyceride and LDL, and lower HDL level, compared to slow acetylator rats ( Hong et al, 2020 ). Rapid acetylator rats also displayed a significantly higher total cholesterol-to-HDL ratio ( Hong et al, 2020 ). Notably, the total cholesterol-to-HDL ratio serves as important indicators of cardiovascular risk ( Millán et al, 2009 ).…”

Section: Evidence Supporting the Role Of Nat2 In Lipid And Cholestero...mentioning

confidence: 99%

See 2 more Smart Citations

Non-coding and intergenic genetic variants of human arylamine N-acetyltransferase 2 (NAT2) gene are associated with differential plasma lipid and cholesterol levels and cardiometabolic disorders

2023

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Evidence Supporting the Role Of Nat2 In Lipid And Cholestero...mentioning

confidence: 99%

Section: Evidence Supporting the Role Of Nat2 In Lipid And Cholestero...mentioning

confidence: 99%

Section: Evidence Supporting the Role Of Nat2 In Lipid And Cholestero...mentioning

confidence: 99%

See 1 more Smart Citation

Non-coding and intergenic genetic variants of human arylamine N-acetyltransferase 2 (NAT2) gene are associated with differential plasma lipid and cholesterol levels and cardiometabolic disorders

2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…2e,f), an increased predicted activity of the N-acetyltransferase pathway (Supplementary Fig. 15b), previously implicated in cardiac dysfunction 29 . In addition, group 3 patients exhibited an increase in glutathione derivative biosynthetic processes, related to the cellular capacity to compensate against reactive oxygen species as well as a reduction in predicted gene activities related to ventricular system development (Fig.…”

Section: Genetically Defined Patient Groups Differ In Disease Relevan...mentioning

confidence: 77%

Distinct genetic liability profiles define clinically relevant patient strata across common diseases

Trastulla

Moser

Jiménez-Barrón

et al. 2023

Preprint

View full text Add to dashboard Cite

Genome-wide association studies have unearthed a wealth of genetic associations across many complex diseases. However, translating these associations into biological mechanisms contributing to disease etiology and heterogeneity has been challenging. Here, we hypothesize that the effects of disease-associated genetic variants converge onto distinct cell type specific molecular pathways within distinct subgroups of patients. In order to test this hypothesis, we develop the CASTom-iGEx pipeline to operationalize individual level genotype data to interpret personal polygenic risk and identify the genetic basis of clinical heterogeneity. The paradigmatic application of this approach to coronary artery disease and schizophrenia reveals a convergence of disease associated variant effects onto known and novel genes, pathways, and biological processes. The biological process specific genetic liabilities are not equally distributed across patients. Instead, they defined genetically distinct groups of patients, characterized by different profiles across pathways, endophenotypes, and disease severity. These results provide further evidence for a genetic contribution to clinical heterogeneity and point to the existence of partially distinct pathomechanisms across patient subgroups. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine concepts.

show abstract

N-acetyltransferase 2 genetic polymorphism modifies genotoxic and oxidative damage from new psychoactive substances

2022

View full text Add to dashboard Cite

Acetylator Genotype-Dependent Dyslipidemia in Rats Congenic for N-Acetyltransferase 2

Abstract: Graphical abstract

Cited by 7 publications

References 62 publications

Non-coding and intergenic genetic variants of human arylamine N-acetyltransferase 2 (NAT2) gene are associated with differential plasma lipid and cholesterol levels and cardiometabolic disorders

Non-coding and intergenic genetic variants of human arylamine N-acetyltransferase 2 (NAT2) gene are associated with differential plasma lipid and cholesterol levels and cardiometabolic disorders

Distinct genetic liability profiles define clinically relevant patient strata across common diseases

N-acetyltransferase 2 genetic polymorphism modifies genotoxic and oxidative damage from new psychoactive substances

Contact Info

Product

Resources

About