The DOI matches its Crossref record; 161 of the 161 references it cites were found in a registry or an index.
Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes
Open accessAbstract
Free fatty acids (FFAs) are important substrates for mitochondrial oxidative metabolism and ATP synthesis but also cause serious stress to various tissues, contributing to the development of metabolic diseases. CD36 is a major mediator of cellular FFA uptake. Inside the cell, saturated FFAs are able to induce the production of cytosolic and mitochondrial reactive oxygen species (ROS), which can be prevented by co-exposure to unsaturated FFAs. There are close connections between oxidative stress and organellar Ca2+ homeostasis. Highly oxidative conditions induced by palmitate trigger aberrant endoplasmic reticulum (ER) Ca2+ release and thereby deplete ER Ca2+ stores. The resulting ER Ca2+ deficiency impairs chaperones of the protein folding machinery, leading to the accumulation of misfolded proteins. This ER stress may further aggravate oxidative stress by augmenting ER ROS production. Secondary to ER Ca2+ release, cytosolic and mitochondrial matrix Ca2+ concentrations can also be altered. In addition, plasmalemmal ion channels operated by ER Ca2+ depletion mediate persistent Ca2+ influx, further impairing cytosolic and mitochondrial Ca2+ homeostasis. Mitochondrial Ca2+ overload causes superoxide production and functional impairment, culminating in apoptosis. This vicious cycle of lipotoxicity occurs in multiple tissues, resulting in β-cell failure and insulin resistance in target tissues, and further aggravates diabetic complications. High levels of the fatty acid palmitate cause cell death and exacerbate the complications of type 2 diabetes. Kyu-Sang Park at Yonsei University Wonju College of Medicine and colleagues review the molecular mechanisms responsible for palmitate-induced toxicity. The transmembrane protein CD36 mediates the uptake of palmitate into cells where it triggers the production of reactive oxygen species (ROS). Overproduction of ROS interferes with the cell's protein-processing organelle, the endoplasmic reticulum (ER), leading to damaged misfolded proteins and to ER calcium loss. This loss further damages protein folding and increases ROS production. Moreover, it causes an influx of calcium into mitochondria, the cell's power plants, and ultimately results in cell death. Therapeutic agents that inhibit CD36, reduce ROS production or prevent ER calcium loss could break this toxic cycle and contribute to the treatment of type 2 diabetes.
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“ROS accumulation triggers damaging cascades: a decrease in mitochondrial membrane potential, activation of caspases 3/7, apoptosis, and ER stress and inflammation via NF-κB [90,152,153,154,155].”
From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [153]
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Citations
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Role of Minerals and Trace Elements in Diabetes and Insulin Resistance
Dubey, P., Thakur, V., & Chattopadhyay, M. (2020) · Nutrients · doi:10.3390/nu12061864 · Cited by 407
Piao, M. J., Ahn, M. J., Kang, K. A., Ryu, Y. S., Hyun, Y. J., Shilnikova, K., Zhen, A. X., Jeong, J. W., Choi, Y. H., Kang, H. K., et al. (2018) · Archives of Toxicology · doi:10.1007/s00204-018-2197-9 · Cited by 339
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The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes
Eguchi, N., Vaziri, N. D., Dafoe, D. C., & Ichii, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041509 · Cited by 367
The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling
Bhattarai, K. R., Riaz, T. A., Kim, H., & Chae, H. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00560-8 · Cited by 356
Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes
Oh, Y. S., Bae, G. D., Baek, D. J., Park, E., & Jun, H. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00384 · Cited by 323
Metadata
- Authors
- Ly, L. D., Xu, S., Choi, S.-K., Ha, C.-M., Thoudam, T., Cha, S.-K., Wiederkehr, A., Wollheim, C. B., Lee, I.-K., & Park, K.-S.
- Affiliations
- Yonsei University (KR)
- Kyungpook National University Hospital (KR)
- University of Geneva (CH)
- Corresponding author
- Park, Kyu-Sang
- ORCID
- Venue
- Experimental & Molecular Medicine
- Published
- 2017-02-03
- Volume
- 49
- Issue
- 2
- Pages
- e291-e291
- ISSN
- 1226-3613 (ISSN-L)
- 2092-6413
- PMC
- PMC5336562
- OpenAlex
- W2584561009
- Cited by
- 378
- References
- 161
- Citations by year
- 2026: 30 · 2025: 44 · 2024: 36 · 2023: 53 · 2022: 42 · 2021: 60 · 2020: 39 · 2019: 35 · 2018: 32 · 2017: 5
- FWCI
- 3.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Experimental & Molecular Medicine (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Korea Health Industry Development Institute (HI16C1501)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- palmitate, lipotoxicity, type 2 diabetes, oxidative stress, calcium homeostasis, CD36, free fatty acids, reactive oxygen species, endoplasmic reticulum calcium depletion, endoplasmic reticulum stress, protein misfolding, mitochondrial calcium overload, apoptosis, beta-cell failure, insulin resistance, unsaturated fatty acids
- MeSH terms
- Animals, Calcium, Diabetes Mellitus, Type 2, Endoplasmic Reticulum, Fatty Acids, Nonesterified, Humans, Mitochondria, Palmitic Acids, Reactive Oxygen Species, Oxidative Stress, CD36 Antigens, Insulin-Secreting Cells, Endoplasmic Reticulum Stress
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