Peroxisome-generated hydrogen peroxide as important mediator of lipotoxicity in insulin-producing cells
Open accessAbstract
OBJECTIVE: Type 2 diabetes is a complex disease that is accompanied by elevated levels of nonesterified fatty acids (NEFAs), which contribute to β-cell dysfunction and β-cell loss, referred to as lipotoxicity. Experimental evidence suggests that oxidative stress is involved in lipotoxicity. In this study, we analyzed the molecular mechanisms of reactive oxygen species-mediated lipotoxicity in insulin-producing RINm5F cells and INS-1E cells as well as in primary rat islet cells. RESEARCH DESIGN AND METHODS: The toxicity of saturated NEFAs with different chain lengths upon insulin-producing cells was determined by MTT and propidium iodide (PI) viability assays. Catalase or superoxide dismutase overexpressing cells were used to analyze the nature and the cellular compartment of reactive oxygen species formation. With the new H₂O₂-sensitive fluorescent protein HyPer H₂O₂ formation induced by exposure to palmitic acid was determined. RESULTS: Only long-chain (>C14) saturated NEFAs were toxic to insulin-producing cells. Overexpression of catalase in the peroxisomes and in the cytosol, but not in the mitochondria, significantly reduced H₂O₂ formation and protected the cells against palmitic acid-induced toxicity. With the HyPer protein, H₂O₂ generation was directly detectable in the peroxisomes of RINm5F and INS-1E insulin-producing cells as well as in primary rat islet cells. CONCLUSIONS: The results demonstrate that H₂O₂ formation in the peroxisomes rather than in the mitochondria are responsible for NEFA-induced toxicity. Therefore, we propose a new concept of fatty acid-induced β-cell lipotoxicity mediated via reactive oxygen species formation through peroxisomal β- oxidation.
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Exogenously added palmitate can stimulate H2O2 production in peroxisomes of insulin-producing cells.
“Exogenously added palmitate can stimulate H2O2 production in peroxisomes of insulin-producing cells [34]”
From Peroxisomes in brain development and function (2016) · cites this paper as [34]
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- Authors
- Elsner, M., Gehrmann, W., & Lenzen, S.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Corresponding author
- Lenzen, Sigurd
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2010-10-22
- Volume
- 60
- Issue
- 1
- Pages
- 200-208
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3012172
- OpenAlex
- W2127998841
- Cited by
- 221
- References
- 54
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 13 · 2023: 8 · 2022: 17 · 2021: 27 · 2020: 17 · 2019: 17 · 2018: 10 · 2017: 16 · 2016: 13 · 2015: 17 · 2014: 13 · 2013: 13 · 2012: 17
- FWCI
- 13.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- European Commission (LSHM-CT-2006-518153)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- lipotoxicity, insulin-producing cells, free fatty acids, palmitic acid, reactive oxygen species, peroxisomal beta-oxidation, beta-cell dysfunction, type 2 diabetes, oxidative stress, catalase, superoxide dismutase, RINm5F cells, INS-1E cells
- MeSH terms
- Peroxisome-Targeting Signal 1 Receptor, Animals, Cell Survival, Extracellular Matrix, Fluoresceins, Humans, Hydrogen Peroxide, Immunohistochemistry, Islets of Langerhans, Male, Rats, Inbred Lew, Lentivirus, Polymerase Chain Reaction, DNA Primers, Receptors, Cytoplasmic and Nuclear, Oxidative Stress, Cell Culture Techniques, Peroxisomes, Insulin-Secreting Cells, Rats, Hep G2 Cells
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