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Genetic inhibition of nicotinamide N-methyltransferase and prevention of alcohol-associated fatty liver in humans

Journal of Human Genetics volume 70, pages 141–146 (2025)Cite this article

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Abstract

Recent studies of animal models reported Nicotinamide N-methyltransferase (NNMT) as a potential therapeutic target for preventing alcohol-associated fatty liver (AFL), yet its efficacy and safety in humans remain unknown. We aim to estimate the effectiveness and safety of inhibiting NNMT in humans. We leveraged Electronic Medical Records (EMRs) data coupled with genetic information to perform a retrospective drug target validation study. We examined longitudinal clinical data from 612 individuals with excessive alcohol consumption. Two variants lowering NNMT protein levels were combined to calculate a weighted NNMT genetic score that could mimic mild inhibition of NNMT. Participants with an NNMT score above the median were classified as genetically inhibited, while others were considered non-inhibited. We then evaluated whether genetic inhibition of NNMT would affect the incidence of AFL or the risk of liver injury, to illuminate the effectiveness and safety of genetic inhibition of NNMT respectively. NNMT genetic inhibition correlated with a reduced AFL risk (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.49–0.90, P = 0.009) without a significant increase in serum aminotransferase levels (P > 0.10). Notably, elevated ALT and AST levels were observed (P < 0.05) in the genetically inhibited group prior to alcohol exposure. These findings suggest NNMT inhibition is a promising avenue for AFL prevention among individuals with excessive alcohol intake. They also underscore the need for precise target population identification to mitigate potential adverse effects.

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Data availability

The datasets used and analyzed during the current study available from the corresponding author on reasonable request.

References

  1. Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol. 2013;59:160–8.

    Article  PubMed  Google Scholar 

  2. Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, et al. Alcoholic liver disease. Nat Rev Dis Prim. 2018;4:16.

    Article  PubMed  Google Scholar 

  3. Mackowiak B, Fu Y, Maccioni L, Gao B. Alcohol-associated liver disease. J Clin Invest [Internet]. 2024 Feb 1 [cited 2024 Nov 5];134. Available from: https://www.jci.org/articles/view/176345.

  4. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011;141:1572–85.

    Article  CAS  PubMed  Google Scholar 

  5. Pissios P. Nicotinamide N-methyltransferase: more than a vitamin B3 clearance enzyme. Trends Endocrinol Metab. 2017;28:340–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Roberti A, Fernández AF, Fraga MF. Nicotinamide N-methyltransferase: at the crossroads between cellular metabolism and epigenetic regulation. Mol Metab. 2021;45:101165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Longato L, Ripp K, Setshedi M, Dostalek M, Akhlaghi F, Branda M, et al. Insulin resistance, ceramide accumulation, and endoplasmic reticulum stress in human chronic alcohol-related liver disease. Oxid Med Cell Longev. 2012;2012:e479348.

    Article  Google Scholar 

  8. Kaplowitz N, Than TA, Shinohara M, Ji C. Endoplasmic reticulum stress and liver injury. Semin Liver Dis. 2007;27:367–77.

    Article  CAS  PubMed  Google Scholar 

  9. Ji C, Kaplowitz N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology. 2003;124:1488–99.

    Article  CAS  PubMed  Google Scholar 

  10. Kono H, Rusyn I, Yin M, Gäbele E, Yamashina S, Dikalova A, et al. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest. 2000;106:867–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kraus D, Yang Q, Kong D, Banks AS, Zhang L, Rodgers JT, et al. Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity. Nature. 2014;508:258–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Komatsu M, Kanda T, Urai H, Kurokochi A, Kitahama R, Shigaki S, et al. NNMT activation can contribute to the development of fatty liver disease by modulating the NAD + metabolism. Sci Rep. 2018;8:8637.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Song Q, Chen Y, Wang J, Hao L, Huang C, Griffiths A, et al. ER stress-induced upregulation of NNMT contributes to alcohol-related fatty liver development. J Hepatol. 2020;73:783–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ding Q, Ma Y, Lai S, Dou X, Li S. NNMT aggravates hepatic steatosis, but alleviates liver injury in alcoholic liver disease. J Hepatol. 2021;74:1248–50.

    Article  CAS  PubMed  Google Scholar 

  15. Sidor K, Jeznach A, Hoser G, Skirecki T. 1-Methylnicotinamide (1-MNA) inhibits the activation of the NLRP3 inflammasome in human macrophages. Int Immunopharmacol. 2023;121:110445.

    Article  CAS  PubMed  Google Scholar 

  16. Biedroń R, Ciszek M, Tokarczyk M, Bobek M, Kurnyta M, Słominska EM, et al. 1-Methylnicotinamide and nicotinamide: two related anti-inflammatory agents that differentially affect the functions of activated macrophages. Arch Immunol Ther Exp. 2008;56:127–34.

    Article  Google Scholar 

  17. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov. 2010;9:203–14.

    Article  CAS  PubMed  Google Scholar 

  18. McGonigle P, Ruggeri B. Animal models of human disease: challenges in enabling translation. Biochem Pharmacol. 2014;87:162–71.

    Article  CAS  PubMed  Google Scholar 

  19. Plenge RM, Scolnick EM, Altshuler D. Validating therapeutic targets through human genetics. Nat Rev Drug Discov. 2013;12:581–94.

    Article  CAS  PubMed  Google Scholar 

  20. Koscielny G, An P, Carvalho-Silva D, Cham JA, Fumis L, Gasparyan R, et al. Open Targets: a platform for therapeutic target identification and validation. Nucleic Acids Res. 2017;45:D985–94.

    Article  CAS  PubMed  Google Scholar 

  21. Tian Z, Chen F, Wang J, Wu B, Shao J, Liu Z, et al. CAS Array: design and assessment of a genotyping array for Chinese biobanking. Precis Clin Med. 2023;6:pbad002.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ferkingstad E, Sulem P, Atlason BA, Sveinbjornsson G, Magnusson MI, Styrmisdottir EL, et al. Large-scale integration of the plasma proteome with genetics and disease. Nat Genet. 2021;53:1712–21.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang J, Dutta D, Köttgen A, Tin A, Schlosser P, Grams ME, et al. Plasma proteome analyses in individuals of European and African ancestry identify cis-pQTLs and models for proteome-wide association studies. Nat Genet. 2022;54:593–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36:1–48.

    Article  Google Scholar 

  25. Schwenzer NF, Springer F, Schraml C, Stefan N, Machann J, Schick F. Non-invasive assessment and quantification of liver steatosis by ultrasound, computed tomography and magnetic resonance. J Hepatol. 2009;51:433–45.

    Article  PubMed  Google Scholar 

  26. Sherman KE. Alanine aminotransferase in clinical practice: a review. Arch Intern Med. 1991;151:260–5.

    Article  CAS  PubMed  Google Scholar 

  27. McGill MR. The past and present of serum aminotransferases and the future of liver injury biomarkers. EXCLI J. 2016;15:817–28.

    PubMed  PubMed Central  Google Scholar 

  28. Holmes RS, Duley JA, Algar EM, Mather PB, Rout UK. Biochemical and genetic studies on enzymes of alcohol metabolism: the mouse as a model organism for human studies. Alcohol Alcohol. 1986;21:41–56.

    CAS  PubMed  Google Scholar 

  29. Liu SX, Du YC, Zeng T. A mini-review of the rodent models for alcoholic liver disease: shortcomings, application, and future prospects. Toxicol Res. 2021;10:523–30.

    Article  Google Scholar 

  30. Mestas J, Hughes CCW. Of mice and not men: differences between mouse and human immunology. J Immunol. 2004;172:2731–8.

    Article  CAS  PubMed  Google Scholar 

  31. Hines IN, Wheeler MD. Recent advances in alcoholic liver disease III. Role of the innate immune response in alcoholic hepatitis. Am J Physiol-Gastrointest Liver Physiol. 2004;287:G310–4.

    Article  CAS  PubMed  Google Scholar 

  32. Altamirano J, Bataller R. Alcoholic liver disease: pathogenesis and new targets for therapy. Nat Rev Gastroenterol Hepatol. 2011;8:491–501.

    Article  CAS  PubMed  Google Scholar 

  33. Monticello TM, Jones TW, Dambach DM, Potter DM, Bolt MW, Liu M, et al. Current nonclinical testing paradigm enables safe entry to First-In-Human clinical trials: The IQ consortium nonclinical to clinical translational database. Toxicol Appl Pharmacol. 2017;334:100–9.

    Article  CAS  PubMed  Google Scholar 

  34. Jakubowski A, Sternak M, Jablonski K, Ciszek-Lenda M, Marcinkiewicz J, Chlopicki S. 1-Methylnicotinamide protects against liver injury induced by concanavalin A via a prostacyclin-dependent mechanism: A possible involvement of IL-4 and TNF-α. Int Immunopharmacol. 2016;31:98–104.

    Article  CAS  PubMed  Google Scholar 

  35. Taniki N, Nakamoto N, Chu PS, Mikami Y, Amiya T, Teratani T, et al. Intestinal barrier regulates immune responses in the liver via IL-10–producing macrophages. JCI Insight [Internet]. 2018 Jun 21 [cited 2024 Jan 22];3. Available from: https://insight.jci.org/articles/view/91980.

  36. Sarich P, Canfell K, Banks E, Paige E, Egger S, Joshy G, et al. A prospective study of health conditions related to alcohol consumption cessation among 97,852 drinkers aged 45 and over in Australia. Alcohol: Clin Exp Res. 2019;43:710–21.

    Article  PubMed  Google Scholar 

  37. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med. 2003;168:1308–11.

    Article  PubMed  Google Scholar 

  38. Chalmers GW, Macleod KJ, Little SA, Thomson LJ, McSharry CP, Thomson NC. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax. 2002;57:226–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Becker U, Deis A, Sorensen TI, Gronbaek M, Borch-Johnsen K, Muller CF, et al. Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology. 1996;23:1025.

    Article  CAS  PubMed  Google Scholar 

  40. Palmentieri B, Desio I, Lamura V, Masarone M, Vecchione R, Bruno S, et al. The role of bright liver echo pattern on ultrasound B-mode examination in the diagnosis of liver steatosis. Digestive Liver Dis. 2006;38:485–9.

    Article  CAS  Google Scholar 

  41. Wang J, Lin X, Bloomgarden ZT, Ning G. The Jiangnan diet, a healthy diet pattern for Chinese. [cited 2024 Nov 7]; Available from: https://onlinelibrary.wiley.com/doi/10.1111/1753-0407.13015.

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Acknowledgements

This work was funded by the National High Level Hospital Clinical Research Funding (BJ-2024-144) and Kunshan Key Research and Development Project (KS2214). The funders played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript.

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Author notes

  1. These authors contributed equally: Benrui Wu, Xiong Weng.

Authors and Affiliations

  1. National Laboratory of Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, China

    Benrui Wu, Zijian Tian, Yiying Liu & Tao Xu

  2. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China

    Benrui Wu, Zijian Tian & Yiying Liu

  3. Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, Scotland

    Xiong Weng

  4. Department of general practice, Kunshan Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu, China

    Ying Pan

  5. Guangzhou Laboratory, Guangzhou International Bio Island, Guangzhou, China

    Peng Wu, Jian Shao, Tao Xu & Kaixin Zhou

  6. Medical Science and Technology Innovation Center, Jinan Central Hospital, Shandong First Medical University, Jinan, Shandong, China

    Rong Huang

  7. College of Public Health, Guangzhou Medical University, Guangzhou, China

    Kaixin Zhou

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  1. Benrui Wu
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Contributions

KZ and TX were responsible for study conception and design; BRW contributed to the researched data, discussion, and data interpretation and wrote the manuscript. XW contributed to the discussion, data interpretation, review and editing the manuscript; YP, ZT, PW, JS, YL and RH contributed to the genetic analysis.

Corresponding authors

Correspondence to Tao Xu or Kaixin Zhou.

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The authors declare no competing interests.

Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the First People’s Hospital of Kunshan, Approval No. 2019-03-001-K01. Informed consent was obtained from all individual participants included in the study.

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Wu, B., Weng, X., Pan, Y. et al. Genetic inhibition of nicotinamide N-methyltransferase and prevention of alcohol-associated fatty liver in humans. J Hum Genet 70, 141–146 (2025). https://doi.org/10.1038/s10038-024-01313-x

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