ArticleJournal of hepatology2023
IL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease.
Article in Journal of hepatology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers, 2 of them syntheses that pooled it.
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Who cites it
81 citing papers in PubMed, 2 syntheses or guidelines pooled it, 123 citations in OpenAlex.
- Research trends on the quality of life in patients with metabolic dysfunction-associated fatty liver diseases: a scientific metrology study.Frontiers in nutrition · 2025Pooled it
- Titanium dioxide nanoparticles: revealing the mechanisms underlying hepatotoxicity and effects in the gut microbiota.Archives of toxicology · 2023Pooled it
- Hepatic steatosis affects the outcome of anti-tuberculosis treatment in pulmonary tuberculosis patients.Journal of clinical tuberculosis and other mycobacterial diseases · 2026Article
- Impact of hypertriglyceridemia on right ventricular deformation in patients with left ventricular myocardial infarction: a cardiac magnetic resonance imaging study.Quantitative imaging in medicine and surgery · 2026Article
- IRF2 exacerbates diabetic neuropathic pain by promoting high glucose-induced M1 polarization through IL-6/STAT3.Genes & genomics · 2026Article
- Fluorescent protein ticker tape (FPTT): Multiplexed recording of transcriptional dynamics in living cells and in vivo.Science advances · 2026Article
- Mesenchymal stem cell-induced metabolic reprogramming of EGFR-wild-type tumor cells drives therapeutic resistance in EGFR-mutant non-small cell lung cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- Mechanistic insights and evidence-based management of metabolic dysfunction-associated steatotic liver disease (MASLD; formerly NAFLD) through combined diet and exercise interventions: an evidence-based narrative review.Journal of clinical biochemistry and nutrition · 2026Review
- Germline mutations and somatic mosaicism in steatotic liver diseases and related liver carcinogenesis.Nature reviews. Gastroenterology & hepatology · 2026Review
- Exosomal ORF3a mediates lung-liver axis to dysregulate hepatic lipid metabolism in mild COVID-19.Cell discovery · 2026Article
- The role of hepatocyte epigenetics in the pathogenesis of metabolic dysfunction-associated steatotic liver disease.Communications medicine · 2026Review
- Reimagining human-centric drug development with new approach methodologies.Science (New York, N.Y.) · 2026Review
- Integrated Transcriptomics and Machine Learning Reveal Lipid Metabolism Related Genes in Ischemic Stroke.Journal of molecular neuroscience : MN · 2026Article
- Mechanism of arbutin in metabolic dysfunction-associated fatty liver disease based on multi-omics research.Bioresources and bioprocessing · 2026Article
- Apigenin combined with aerobic exercise alleviates oxidative stress and inflammation in high-fat diet-induced NAFLD mice by modulating the Keap1/Nrf2/ARE pathway.Scientific reports · 2026Article
- Genetic modulators of metabolic dysfunction-associated steatotic liver disease (MASLD) and their epistatic interactions: from in vitro and animal models to clinical outcomes.BMC medical genomics · 2026Review
- A PNPLA3-NACC1-RIPK3 pathway mediates macrophage necroptosis and inflammation in MASLD.Hepatology communications · 2026Article
- Single-cell analysis of heterogeneity in reverted hiPSC-derived human hepatic stellate cells.JHEP reports : innovation in hepatology · 2026Article
- Si-Ni-San improves the deposition of lipid droplets in MAFLD through modulating the FXR-GPAT4 axis.Chinese medicine · 2026Article
- Modeling fatty liver disease and progression with stem cell derived hepatocytes.Scientific reports · 2026Article
21 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 7 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsA number of genetic polymorphisms have been associated with susceptibility to or protection against non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms remain unknown. Here, we focused on the rs738409 C>G single nucleotide polymorphism (SNP), which produces the I148M variant of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and is strongly associated with NAFLD.
methodsTo enable mechanistic dissection, we developed a human pluripotent stem cell (hPSC)-derived multicellular liver culture by incorporating hPSC-derived hepatocytes, hepatic stellate cells, and macrophages. We first applied this liver culture to model NAFLD by utilising a lipotoxic milieu reflecting the circulating levels of disease risk factors in affected individuals. We then created an isogenic pair of liver cultures differing only at rs738049 and compared NAFLD phenotype development.
resultsOur hPSC-derived liver culture recapitulated many key characteristics of NAFLD development and progression including lipid accumulation and oxidative stress, inflammatory response, and stellate cell activation. Under the lipotoxic conditions, the I148M variant caused the enhanced development of NAFLD phenotypes. These differences were associated with elevated IL-6/signal transducer and activator of transcription 3 (STAT3) activity in liver cultures, consistent with transcriptomic data of liver biopsies from individuals carrying the rs738409 SNP. Dampening IL-6/STAT3 activity alleviated the I148M-mediated susceptibility to NAFLD, whereas boosting it in wild-type liver cultures enhanced NAFLD development. Finally, we attributed this elevated IL-6/STAT3 activity in liver cultures carrying the rs738409 SNP to increased NF-κB activity.
conclusionsOur study thus reveals a potential causal link between elevated IL-6/STAT3 activity and 148M-mediated susceptibility to NAFLD. IMPACT AND IMPLICATIONS: An increasing number of genetic variants manifest in non-alcoholic fatty liver disease (NAFLD) development and progression; however, the underlying mechanisms remain elusive. To study these variants in human-relevant systems, we developed an induced pluripotent stem cell-derived multicellular liver culture and focused on a common genetic variant (i.e. rs738409 in PNPLA3). Our findings not only provide mechanistic insight, but also a potential therapeutic strategy for NAFLD driven by this genetic variant in PNPLA3. Our liver culture is therefore a useful platform for exploring genetic variants in NAFLD development.
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