ArticleDiabetes2013
Proteasome dysfunction mediates obesity-induced endoplasmic reticulum stress and insulin resistance in the liver.
Article in Diabetes, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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Who cites it
68 citing papers in PubMed, 131 citations in OpenAlex.
- Molecular Mechanisms of Obesity-Associated Oxidative Stress and Therapeutic Strategies.Antioxidants (Basel, Switzerland) · 2026Review
- Obesity accelerates aging: Mechanisms and therapeutic implications.Genes & diseases · 2026Review
- [Interferon-α induces disulfidptosis occurrence in human liver cancer cells].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2026Article
- Sex-specific effects of acetylation on tauopathy in aging htau mice.Scientific reports · 2026Article
- Insulin resistance: mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
- Therapeutic potential of traditional Chinese medicine and mechanisms for the treatment of type 2 diabetes mellitus.Chinese medicine · 2025Review
- Human iPSC-derived salivary gland organoids model diabetic salivary gland dysfunction.bioRxiv : the preprint server for biology · 2025Article
- Metabolic Dysfunction-Associated Steatotic Liver Disease Complicated by Diabetes: Pathophysiology and Emerging Therapies.Journal of obesity & metabolic syndrome · 2025Review
- Chronic Alcohol Consumption Reprograms Hepatic Metabolism Through Organelle-Specific Acetylation in Mice.Molecular & cellular proteomics : MCP · 2025Article
- Lysosomal Stress in Cardiovascular Diseases: Therapeutic Potential of Cardiovascular Drugs and Future Directions.Biomedicines · 2025Review
- Distinctive blood and salivary proteomics signatures in Qatari individuals at high risk for cardiovascular disease.Scientific reports · 2025Article
- Scars of oxidative stress: protein carbonylation and beta cell dysfunction in diabetes.Frontiers in endocrinology · 2025Review
- Deubiquitinase JOSD1 tempers hepatic proteotoxicity.Cell death discovery · 2024Article
- Ubiquitination and Metabolic Disease.Advances in experimental medicine and biology · 2024Review
- Genetic blockade of the activation of 26S proteasomes by PKA is well tolerated by mice at baseline.American journal of cardiovascular disease · 2024Article
- PAC1 Deficiency Protects Obese Male Mice From Immobilization-Induced Muscle Atrophy by Suppressing FoxO-Atrogene Axis.Endocrinology · 2023Article
- The role of proteasome activators PA28αβ and PA200 in brown adipocyte differentiation and function.Frontiers in endocrinology · 2023Article
- PKR Protects the Major Catalytic Subunit of PKA Cpk1 from FgBlm10-Mediated Proteasome Degradation inInternational journal of molecular sciences · 2022Article
- Antioxidative, Anti-Inflammatory, Anti-Obesogenic, and Antidiabetic Properties of Tea Polyphenols-The Positive Impact of Regular Tea Consumption as an Element of Prophylaxis and Pharmacotherapy Support in Endometrial Cancer.International journal of molecular sciences · 2022Review
- The multifaceted roles of ER and Golgi in metabolic cardiomyopathy.Frontiers in cardiovascular medicine · 2022Review
8 more citing papers are in PubMed but not listed here.
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Authors and funding
24 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chronic endoplasmic reticulum (ER) stress is a major contributor to obesity-induced insulin resistance in the liver. However, the molecular link between obesity and ER stress remains to be identified. Proteasomes are important multicatalytic enzyme complexes that degrade misfolded and oxidized proteins. Here, we report that both mouse models of obesity and diabetes and proteasome activator (PA)28-null mice showed 30-40% reduction in proteasome activity and accumulation of polyubiquitinated proteins in the liver. PA28-null mice also showed hepatic steatosis, decreased hepatic insulin signaling, and increased hepatic glucose production. The link between proteasome dysfunction and hepatic insulin resistance involves ER stress leading to hyperactivation of c-Jun NH₂-terminal kinase in the liver. Administration of a chemical chaperone, phenylbutyric acid (PBA), partially rescued the phenotypes of PA28-null mice. To confirm part of the results obtained from in vivo experiments, we pretreated rat hepatoma-derived H4IIEC3 cells with bortezomib, a selective inhibitor of the 26S proteasome. Bortezomib causes ER stress and insulin resistance in vitro--responses that are partly blocked by PBA. Taken together, our data suggest that proteasome dysfunction mediates obesity-induced ER stress, leading to insulin resistance in the liver.
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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.