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Cited by 138Liver Disease Diagnosis and TreatmentLiver physiology and pathologyDrug-Induced Hepatotoxicity and Protection

IL-6/STAT3 axis dictates the PNPLA3-mediated susceptibility to non-alcoholic fatty liver disease

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Park, Jiwoon, Zhao, Yuanyuan, Zhang, Fan, Zhang, Shaoyan, Kwong, Andrew C., Zhang, Yujie, Hoffmann, Hans-Heinrich, Bushweller, Leila +9 more·2023·Journal of Hepatology
DOI 10.1016/j.jhep.2022.08.022PMC PMC9772150
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Abstract

Background & aims A 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. Methods To 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. Results Our 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. Conclusions Our 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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  • In hPSC-derived liver culture mimicking genetic variant-derived NAFLD, IL-6 expression and IL-6/STAT3 activity are elevated during NAFLD development, and dampening IL-6/STAT3 activity alleviates genetic variant-mediated susceptibility to NAFLD.

    “A recent study used hPSC-derived liver culture to mimic genetic variant-derived NAFLD, and found that IL-6 expression and IL-6/STAT3 activity was elevated during NAFLD development. The dampening of IL-6/STAT3 activity could alleviate the genetic variant-mediated susceptibility to NAFLD [58].”

    From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [58]

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Authors
Park, J., Zhao, Y., Zhang, F., Zhang, S., Kwong, A. C., Zhang, Y., Hoffmann, H.-H., Bushweller, L., Wu, X., Ashbrook, A. W., Stefanovic, B., Chen, S., Branch, A. D., Mason, C. E., Jung, J. U., Rice, C. M., & Wu, X.
Affiliations
  • Weill Cornell Medicine (US)
  • Cleveland Clinic (US)
  • Harvard University (US)
  • Florida State University (US)
  • Rockefeller University (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
  • Rice, Charles M.
  • Wu, Xianfang
ORCID
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2023-01
Volume
78
Issue
1
Pages
45-56
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2022.08.022
PMC
PMC9772150
OpenAlex
W4293522720
Cited by
138
References
7
Citations by year
2026: 32 · 2025: 47 · 2024: 33 · 2023: 23 · 2022: 3
FWCI
19.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hepatology (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (R35CA200422, R01CA251275)
  • National Institute of Allergy and Infectious Diseases (R00AI141742, R01AI152190, R01AI140705, K99AI141742, R01AI140718, R01AI171201, DP2AI170515, R01AI151013)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK125100, R01DK059466)
  • National Institute of Dental and Craniofacial Research (R01DE023926, R01DE028521)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
non-alcoholic fatty liver disease, PNPLA3, rs738409, I148M variant, IL-6/STAT3 signaling, NF-κB, lipotoxicity, hepatic stellate cell activation, hepatocyte inflammation, genetic susceptibility, oxidative stress, lipid accumulation
MeSH terms
Acyltransferases, Humans, Liver, Membrane Proteins, Interleukin-6, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, STAT3 Transcription Factor, Phospholipases A2, Calcium-Independent, Non-alcoholic Fatty Liver Disease

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