Protein-tyrosine Phosphatases Are Involved in Interferon Resistance Associated with Insulin Resistance in HepG2 Cells and Obese Mice
Open accessAbstract
Insulin resistance is a risk factor for non-response to interferon/ribavirin therapy in patients with chronic hepatitis C. The aim of this study was to determine the role played by protein-tyrosine phosphatases (PTPs) in the absence of interferon-α (IFNα) response associated with insulin resistance. We induced insulin resistance by silencing IRS-2 or by treating HepG2 cells with tumor necrosis factor-α (TNFα) and analyzed insulin response by evaluating Akt phosphorylation and IFNα response by measuring Stat-1 tyrosine phosphorylation and 2',5'-oligoadenylate synthase and myxovirus resistance gene expression. The response to IFNα was also measured in insulin-resistant obese mice (high fat diet and ob/ob mice) untreated and treated with metformin. Silencing IRS-2 mRNA induces insulin resistance and inhibits IFNα response. Likewise, TNFα suppresses insulin and IFNα response. Treatment of cells with pervanadate and knocking down PTP-1B restores insulin and IFNα response. Both silencing IRS-2 and TNFα treatment increase PTP and PTP-1B activity. Metformin inhibits PTP and improves IFNα response in insulin-resistant cells. Insulin-resistant ob/ob mice have increased PTP-1B gene expression and activity in the liver and do not respond to IFNα administration. Treatment with metformin improves this response. In HepG2 cells, insulin resistance provokes IFNα resistance, which is associated with an increased PTP-1B activity in the liver. Inhibition of PTP-1B activity with pervanadate and metformin or knocking down PTP-1B reestablishes IFNα response. Likewise, metformin decreases PTP-1B activity and improves response to IFNα in insulin-resistant obese mice. The use of PTP-1B inhibitors may improve the response to IFNα/ribavirin therapy.
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HepG2 cells are characterized by reduced sensitivity to insulin (insulin resistance) under TNFα, high glucose, or prolonged insulin stimulation, with reduced phosphorylation of IR, IRS-1, and Akt, leading to impaired insulin-stimulated glucose uptake and glycogen synthesis.
“HepG2 cells are characterized by reduced sensitivity to insulin (insulin resistance), which has been demonstrated in numerous studies using models induced by tumor necrosis factor-α (TNFα), high glucose concentrations, or prolonged insulin stimulation [119,120,121].”
From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [119]
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- Authors
- García-Ruiz, I., Solís-Muñoz, P., Gómez-Izquierdo, É., Muñoz-Yagüe, M. T., Valverde, Á. M., & Solís-Herruzo, J. A.
- Affiliations
- Universidad Complutense de Madrid (ES)
- Consejo Superior de Investigaciones Científicas (ES)
- ORCID
- Valverde, Ángela M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-06
- Volume
- 287
- Issue
- 23
- Pages
- 19564-19573
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3365992
- OpenAlex
- W1980850523
- Cited by
- 22
- References
- 51
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 2 · 2013: 7 · 2012: 1
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- protein tyrosine phosphatase, PTP1B, interferon resistance, insulin resistance, chronic hepatitis C, interferon-ribavirin therapy, insulin receptor substrate 2, TNF-α, metformin, pervanadate, STAT1 phosphorylation, ob/ob mice, high-fat diet, Akt phosphorylation
- MeSH terms
- Animals, Antiviral Agents, Enzyme Inhibitors, Humans, Hypoglycemic Agents, Insulin Resistance, Male, Metformin, Mice, Obese, Ribavirin, Tumor Necrosis Factor-alpha, Vanadates, Interferon-alpha, Hepatitis C, Chronic, Gene Silencing, STAT1 Transcription Factor, Proto-Oncogene Proteins c-akt, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Insulin Receptor Substrate Proteins, Gene Knockdown Techniques, Hep G2 Cells
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