ArticleJournal of hepatology2020
ER stress-induced upregulation of NNMT contributes to alcohol-related fatty liver development.
Article in Journal of hepatology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 96 citations in OpenAlex.
- NNMT enhances hyperandrogenism in polyendocrine metabolic ovarian syndrome through epigenetic remodelling.Nature metabolism · 2026Article
- Hepatic PDIA5 improves hyperglycaemia and insulin resistance through stabilisation of ATF6.Diabetologia · 2026Article
- Ethanol‑specific stress and RAB25/GCN1 signaling: Emerging perspectives in alcohol‑associated liver disease: Editorial on "RAB25/GCN1 signaling promotes endoplasmic reticulum stress to mediate alcohol-associated liver disease progression".Clinical and molecular hepatology · 2026Article
- NNMT and the methylation sink: integrating metabolism, epigenetics and immunity in cancer.BMC medicine · 2026Review
- Hepatic Hamp restoration contributes to nicotinamide mononucleotide (NMN)-alleviated hepatic steatosis in chronic alcohol-fed mice.Communications biology · 2026Article
- Nicotinamide mononucleotide attenuates hepatic endoplasmic reticulum stress and modulates circadian rhythms in young mice with diet-induced obesity.Nutrition research and practice · 2026Article
- Low-dose galactose rebalances HBP-mTORC1-SREBP-1c signaling to suppress hepatic lipogenesis and protect against early-stage alcohol-related liver disease.American journal of physiology. Gastrointestinal and liver physiology · 2026Article
- β-sitosterol attenuates hepatic lipid accumulation and fibrosis via NLRP3 signaling in MASH mice.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Krüppel-like factor 15 ameliorates alcohol-induced liver injury in mice via regulation of the PFKFB3/AKT axis.Acta pharmacologica Sinica · 2026Article
- Multi-omics analysis identifies a hepatocyte-associated signature in alcohol-related liver injury.Frontiers in immunology · 2026Article
- A novel glucose-lipid metabolism-related indicator and its association with metabolic dysfunction-associated fatty liver disease: a cross-sectional study based on a health check-up population.Frontiers in endocrinology · 2026Article
- NAD + in fatty liver disease: mechanistic insights and associated targets.Cell biology and toxicology · 2025Review
- Nicotinamide N-Methyltransferase in Cardiovascular Diseases: Metabolic Regulator and Emerging Therapeutic Target.Biomolecules · 2025Review
- Hepatic NMNAT1 is required to defend against alcohol-associated fatty liver disease.Science advances · 2025Article
- NNMT/1-MNA protects against hepatic ischemia-reperfusion injury through the AKT/FOXO1/ANGPT2/JNK axis.Nature communications · 2025Article
- Genetic inhibition of nicotinamide N-methyltransferase and prevention of alcohol-associated fatty liver in humans.Journal of human genetics · 2025Article
- NADK as a molecular marker to distinguish between alcohol- and non-alcohol-associated liver cirrhosis: A pilot study.Clinical and experimental hepatology · 2025Article
- Oxidative stress modulation in alcohol-related liver disease: From chinese botanical drugs to exercise-based interventions.Frontiers in pharmacology · 2025Review
- Molecular regulators of alcoholic liver disease: a comprehensive analysis of microRNAs and long non-coding RNAs.Frontiers in medicine · 2025Review
- Activated AXL Ameliorates Alcohol-associated Steatotic Liver Ischemia-Reperfusion Injury by Inhibiting ER stress and Mitochondria-associated Apoptosis.International journal of biological sciences · 2025Article
4 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsN-nicotinamide methyltransferase (NNMT) is emerging as an important enzyme in the regulation of metabolism. NNMT is highly expressed in the liver. However, the exact regulatory mechanism(s) underlying NNMT expression remains unclear and its potential involvement in alcohol-related liver disease (ALD) is completely unknown.
methodsBoth traditional Lieber-De Carli and the NIAAA mouse models of ALD were employed. A small-scale chemical screening assay and a chromatin immunoprecipitation assay were performed. NNMT inhibition was achieved via both genetic (adenoviral short hairpin RNA delivery) and pharmacological approaches.
resultsChronic alcohol consumption induces endoplasmic reticulum (ER) stress and upregulates NNMT expression in the liver. ER stress inducers upregulated NNMT expression in both AML12 hepatocytes and mice. PERK-ATF4 pathway activation is the main contributor to ER stress-mediated NNMT upregulation in the liver. Alcohol consumption fails to upregulate NNMT in liver-specific Atf4 knockout mice. Both adenoviral NNMT knockdown and NNMT inhibitor administration prevented fatty liver development in response to chronic alcohol feeding; this was also associated with the downregulation of an array of genes involved in de novo lipogenesis, including Srebf1, Acaca, Acacb and Fasn. Further investigations revealed that activation of the lipogenic pathway by NNMT was independent of its NAD
conclusionsER stress, specifically PERK-ATF4 pathway activation, is mechanistically involved in hepatic NNMT upregulation in response to chronic alcohol exposure. Overexpression of NNMT in the liver plays an important role in the pathogenesis of ALD. LAY SUMMARY: In this study, we show that nicotinamide methyltransferase (NNMT) - the enzyme that catalyzes nicotinamide degradation - is a pathological regulator of alcohol-related fatty liver development. NNMT inhibition protects against alcohol-induced fatty liver development and is associated with suppressed de novo lipogenic activity and enhanced AMPK activation. Thus, our data suggest that NNMT may be a potential therapeutic target for the treatment of alcohol-related liver disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.