Activation of the GP130-STAT3 axis and its potential implications in nonalcoholic fatty liver disease
Open accessAbstract
The status of the GP130-STAT3 signaling pathway in humans with nonalcoholic fatty liver disease (NAFLD) and its relevance to disease pathogenesis are unknown. The expression of the gp130-STAT3 axis and gp130 cytokine receptors were studied in subjects with varying phenotypes of NAFLD including nonalcoholic steatohepatitis (NASH) and compared with lean and weight-matched controls without NAFLD. Gp130 and its downstream signaling element (Tyk2 and STAT3) expression were inhibited in obese controls whereas they were increased in NAFLD. IL-6 levels were increased in NASH and correlated with gp130 expression (P < 0.01). Palmitate inhibited gp130-STAT3 expression and signaling. IL-6 and palmitate inhibited hepatic insulin signaling via STAT3-dependent and independent mechanisms, respectively. STAT3 overexpression reversed palmitate-induced lipotoxicity by increasing autophagy (ATG7) and decreasing endoplasmic reticulum stress. These data demonstrate that the STAT3 pathway is activated in NAFLD and can worsen insulin resistance while protecting against other lipotoxic mechanisms of disease pathogenesis.
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Activated IL-6/STAT3 in non-alcoholic fatty liver disease is associated with increased insulin resistance.
“Activated IL-6/STAT3 in non-alcoholic fatty liver disease is associated with increased insulin resistance”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Min et al., 2015
Cites
Reactive oxygen species have a causal role in multiple forms of insulin resistance
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Interleukin-6 induces cellular insulin resistance in hepatocytes.
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Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“Activated IL-6/STAT3 in non-alcoholic fatty liver disease is associated with increased insulin resistance (Min et al., 2015).”
BackgroundHou, X., Yin, S., Ren, R., Liu, S., Yong, L., Liu, Y., Li, Y., Zheng, M., Kunos, G., Gao, B., et al. (2021) · Hepatology · doi:10.1002/hep.31658 · Cited by 223 · see citing works
- Authors
- Min, H.-K., Mirshahi, F., Verdianelli, A., Pacana, T., Patel, V., Park, C.-G., Choi, A., Lee, J.-H., Park, C.-B., Ren, S., & Sanyal, A. J.
- Affiliations
- Virginia Commonwealth University (US)
- Rural Development Administration (KR)
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, Rural Development Administration, Eumseong, Chungbuk, Republic of Korea
- Corresponding author
- Sanyal, Arun J.
- ORCID
- Venue
- American Journal of Physiology-Gastrointestinal and Liver Physiology
- Publisher
- American Physiological Society
- Published
- 2015-05-01
- Volume
- 308
- Issue
- 9
- Pages
- G794-G803
- ISSN
- 0193-1857 (ISSN-L)
- 1522-1547
- PMC
- PMC4421014
- OpenAlex
- W1977567991
- Cited by
- 45
- References
- 5
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 1 · 2020: 5 · 2019: 9 · 2018: 7 · 2017: 5 · 2016: 4 · 2015: 1
- FWCI
- 4.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX001874)
- Rural Development Administration
- U.S. Public Health Service (ULITR000058)
- National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007150, R01DK081410)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, interleukin-6, TYK2, palmitate, lipotoxicity, insulin resistance, hepatic insulin signaling, autophagy, ATG7, endoplasmic reticulum stress, obesity
- MeSH terms
- Autophagy-Related Protein 7, Adult, Aged, Dose-Response Relationship, Drug, Female, Humans, Insulin, Insulin Resistance, Liver, Male, Middle Aged, Phenotype, Time Factors, Transfection, Signal Transduction, Interleukin-6, Case-Control Studies, Palmitic Acid, Ubiquitin-Activating Enzymes, Cell Line, Tumor, STAT3 Transcription Factor, Cytokine Receptor gp130, TYK2 Kinase, Endoplasmic Reticulum Stress, Non-alcoholic Fatty Liver Disease
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