Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene

Knowles, Joshua W.; Xie, Weijia; Zhang, Zhongyang; Chennamsetty, Indumathi; Assimes, Themistocles L.; Paananen, Jussi; Hansson, Ola; Pankow, James S.; Goodarzi, Mark O.; Cárcamo-Orive, Iván; Morris, Andrew P.; Chen, Yii Der I.; Mäkinen, Ville-Petteri; Ganna, Andrea; Guo, Xiuqing; Greenawalt, Danielle M.; Lum, Pek Yee; Molony, Cliona; Lind, Lars; Lindgren, Cecilia M.; Raffel, Leslie J.; Tsao, Philip S.; Schadt, Eric E.; Rotter, Jerome I.; Sinaiko, Alan R.; Reaven, Gerald M.; Yang, Xia; Hsiung, Chao A.; Groop, Leif; Cordell, Heather J.; Laakso, Markku; Hao, Ke; Ingelsson, Erik; Frayling, Timothy M.; Weedon, Michael N.; Walker, Mark; Quertermous, Thomas

doi:10.1172/jci85921

Cited by 29 publications

(49 citation statements)

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“…These effects were further exacerbated when NAT1-deficient mice were challenged with a high-fat diet [5]. These studies support the idea that human deficiency of NAT2 (the orthologue of mouse NAT1) may predispose individuals to the onset of type 2 diabetes mellitus (T2DM), and indeed several studies have reported that NAT2 genetic variations correlate with risk of T2DM [3]. However, it should be noted that when NAT2 is deficient, NAT1 may remain present and active in all body cells.…”

supporting

confidence: 76%

A readout of metabolic efficiency in arylamine N‐acetyltransferase‐deficient mice reveals minor energy metabolism changes

et al. 2019

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Recent studies have revealed a possible link between the activities of polymorphic arylamine N‐acetyltransferases (NATs) and energy metabolism. We used a Nat1/Nat2 double knockout (KO) mouse model to demonstrate that ablation of the two Nat genes is associated with modest, intermittent alterations in respiratory exchange rate. Pyruvate tolerance tests show that double KO mice have attenuated hepatic gluconeogenesis when maintained on a high‐fat/high‐sucrose diet. Absence of the two Nat genes also leads to an increase in the hepatic concentration of coenzyme A in mice fed a high‐fat/high‐sucrose diet. Our results suggest a modest involvement of NAT in energy metabolism in mice, which is consistent with the absence of major phenotypic deregulation of energy metabolism in slow human acetylators.

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supporting

confidence: 76%

A readout of metabolic efficiency in arylamine N‐acetyltransferase‐deficient mice reveals minor energy metabolism changes

et al. 2019

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“…We next asked whether these variants were associated with “gold-standard” measures of insulin sensitivity. Having a greater number of risk-alleles from the 53-SNP, 43-SNP or 28-SNP (excluding loci previously implicated in insulin resistance and lipid traits, respectively) genetic scores was strongly associated with (a) lower insulin sensitivity measured by euglycemic clamp or insulin suppression test in 2,764 individuals27 (p-value for 53-SNP genetic score = 4.3 x 10 -06 ; Table 1) and (b) lower insulin sensitivity index in 4,769 individuals with a frequently-sampled oral glucose tolerance test33 (p-value for 53-SNP genetic score = 7.3 x 10 -10 ; Table 1). …”

Section: Resultsmentioning

confidence: 99%

“…4.5 alleles). The association with insulin sensitivity is from 2,764 participants of the GENESIS consortium27 and the association with the insulin sensitivity index is from 4,769 participants of the MAGIC consortium who underwent a frequently sampled oral glucose tolerance test (OGTT)33; the association with type 2 diabetes is from the InterAct, DIAGRAM and UK Biobank studies; the association with coronary heart disease is from the CARDIoGRAM and the C4D consortia. a In MAGIC, insulin sensitivity index (ISI) = 10,000/√ (fasting plasma glucose (mg/dl)×fasting insulin×mean glucose during OGTT (mg/dl)×mean insulin during OGTT) 33 b

In GENESIS, insulin sensitivity was measured by clamp or insulin suppression test using study-specific parameters (e.g.

…”

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

“…Genome-wide studies of gold-standard measures of insulin resistance have been limited by sample size,27 but multiple genomic loci have been associated with fasting insulin levels, a widely-measured marker of insulin resistance 28,29. A subset of these loci were associated with higher triglycerides and lower high-density lipoprotein (HDL) cholesterol,28 which are hallmarks of insulin resistance 13,30.…”

Section: Introductionmentioning

confidence: 99%

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Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance

et al. 2016

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Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin adjusted for BMI, lower HDL cholesterol and higher triglycerides) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy-type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms between common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognised molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important aetiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

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Deletion of arylamine N‐acetyltransferase 1 in MDA‐MB‐231 human breast cancer cells reduces primary and secondary tumor growth in vivo with no significant effects on metastasis

Doll

Ray

Salazar‐González

et al. 2022

Molecular Carcinogenesis

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Arylamine N‐acetyltransferase 1 (NAT1) is frequently upregulated in breast cancer. Previous studies showed that inhibition or depletion of NAT1 in breast cancer cells diminishes anchorage‐independent growth in culture, suggesting that NAT1 contributes to breast cancer growth and metastasis. To further investigate the contribution of NAT1 to growth and cell invasive/migratory behavior, we subjected parental and NAT1 knockout (KO) breast cancer cell lines (MDA‐MB‐231, MCF‐7, and ZR‐75‐1) to multiple assays. The rate of cell growth in suspension was not consistently decreased in NAT1 KO cells across the cell lines tested. Similarly, cell migration and invasion assays failed to produce reproducible differences between the parental and NAT1 KO cells. To overcome the limitations of in vitro assays, we tested parental and NAT1 KO cells in vivo in a xenograft model by injecting cells into the flank of immunocompromised mice. NAT1 KO MDA‐MB‐231 cells produced primary tumors smaller than those formed by parental cells, which was contributed by an increased rate of apoptosis in KO cells. The frequency of lung metastasis, however, was not altered in NAT1 KO cells. When the primary tumors of the parental and NAT1 KO cells were allowed to grow to a pre‐determined size or delivered directly via tail vein, the number and size of metastatic foci in the lung did not differ between the parental and NAT1 KO cells. In conclusion, NAT1 contributes to primary and secondary tumor growth in vivo in MDA‐MB‐231 breast cancer cells but does not appear to affect its metastatic potential.

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Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene

Cited by 29 publications

References 0 publications

A readout of metabolic efficiency in arylamine N‐acetyltransferase‐deficient mice reveals minor energy metabolism changes

A readout of metabolic efficiency in arylamine N‐acetyltransferase‐deficient mice reveals minor energy metabolism changes

Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance

Deletion of arylamine N‐acetyltransferase 1 in MDA‐MB‐231 human breast cancer cells reduces primary and secondary tumor growth in vivo with no significant effects on metastasis

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