Details
| Original language | English |
|---|---|
| Article number | 165525 |
| Journal | Biochimica et biophysica acta: Molecular basis of disease |
| Volume | 1865 |
| Issue number | 11 |
| Early online date | 6 Aug 2019 |
| Publication status | Published - 1 Nov 2019 |
| Externally published | Yes |
Abstract
Lipotoxicity has been considered a major cause for beta-cell dysfunction in type 2 diabetes mellitus. However, the underlying mechanisms are still unclear. To achieve a better understanding of the toxicity a wide range of structurally different free fatty acids (FFAs) has been analyzed in human EndoC-βH1 beta-cells. Exposure of human EndoC-βH1 beta-cells to physiological saturated and monounsaturated long-chain FFAs induced apoptosis. Particularly noteworthy was that the toxicity increased more rapidly with increasing chain length of saturated than of unsaturated FFAs. The highest toxicity was observed in the presence of very long-chain FFAs (C20-C22), whereas polyunsaturated FFAs were not toxic. Long-chain FFAs increased peroxisomal hydrogen peroxide generation slightly, while very long-chain FFAs increased hydrogen peroxide generation more potently in both peroxisomes and mitochondria. The greater toxicity of very long-chain FFAs was accompanied by hydroxyl radical formation, along with cardiolipin peroxidation and ATP depletion. Intriguingly, only saturated very long-chain FFAs activated ER stress. On the other hand saturated very long-chain FFAs did not induce lipid droplet formation in contrast to long-chain FFAs and unsaturated very long-chain FFAs. The present data highlight the importance of structure-activity relationship analyses for the understanding of the mechanisms of lipotoxicity. Chain length and degree of saturation of FFAs are crucial factors for the toxicity of FFAs, with peroxisomal, mitochondrial, and ER stress representing the major pathogenic factors for induction of lipotoxicity. The results might provide a guide for the composition of a healthy beta-cell protective diet.
Keywords
- Apoptosis, Cell Line, Diabetes Mellitus, Type 2/metabolism, Endoplasmic Reticulum Stress, Fatty Acids/chemistry, Fatty Acids, Unsaturated/chemistry, Humans, Insulin-Secreting Cells/cytology, Type 2 diabetes, ER stress, Fatty acid, Lipotoxicity, Human pancreatic beta cell
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
Sustainable Development Goals
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In: Biochimica et biophysica acta: Molecular basis of disease, Vol. 1865, No. 11, 165525, 01.11.2019.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Structure-toxicity relationships of saturated and unsaturated free fatty acids for elucidating the lipotoxic effects in human EndoC-βH1 beta-cells
AU - Plötz, T
AU - von Hanstein, A S
AU - Krümmel, B
AU - Laporte, A
AU - Mehmeti, I
AU - Lenzen, S
N1 - Funding Information: This work was supported by the European Union (Collaborative Project BetaBAT in the Framework Programme 7, grant agreement 277713). T.P. and A.L. have been PhD students within the Research Training Group (RTG) 1947 BiOx of the German Research Council at the University of Greifswald. TP designed and performed experiments, analyzed data, and created figures and tables and co-supervised the project; BK, ASvH, AL performed experiments and analyzed data; IM coordinated and analyzed ER stress experiments; SL designed experiments, and supervised and coordinated the project. TP, IM and SL wrote the manuscript and all other authors revised and approved the final version of the manuscript.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - Lipotoxicity has been considered a major cause for beta-cell dysfunction in type 2 diabetes mellitus. However, the underlying mechanisms are still unclear. To achieve a better understanding of the toxicity a wide range of structurally different free fatty acids (FFAs) has been analyzed in human EndoC-βH1 beta-cells. Exposure of human EndoC-βH1 beta-cells to physiological saturated and monounsaturated long-chain FFAs induced apoptosis. Particularly noteworthy was that the toxicity increased more rapidly with increasing chain length of saturated than of unsaturated FFAs. The highest toxicity was observed in the presence of very long-chain FFAs (C20-C22), whereas polyunsaturated FFAs were not toxic. Long-chain FFAs increased peroxisomal hydrogen peroxide generation slightly, while very long-chain FFAs increased hydrogen peroxide generation more potently in both peroxisomes and mitochondria. The greater toxicity of very long-chain FFAs was accompanied by hydroxyl radical formation, along with cardiolipin peroxidation and ATP depletion. Intriguingly, only saturated very long-chain FFAs activated ER stress. On the other hand saturated very long-chain FFAs did not induce lipid droplet formation in contrast to long-chain FFAs and unsaturated very long-chain FFAs. The present data highlight the importance of structure-activity relationship analyses for the understanding of the mechanisms of lipotoxicity. Chain length and degree of saturation of FFAs are crucial factors for the toxicity of FFAs, with peroxisomal, mitochondrial, and ER stress representing the major pathogenic factors for induction of lipotoxicity. The results might provide a guide for the composition of a healthy beta-cell protective diet.
AB - Lipotoxicity has been considered a major cause for beta-cell dysfunction in type 2 diabetes mellitus. However, the underlying mechanisms are still unclear. To achieve a better understanding of the toxicity a wide range of structurally different free fatty acids (FFAs) has been analyzed in human EndoC-βH1 beta-cells. Exposure of human EndoC-βH1 beta-cells to physiological saturated and monounsaturated long-chain FFAs induced apoptosis. Particularly noteworthy was that the toxicity increased more rapidly with increasing chain length of saturated than of unsaturated FFAs. The highest toxicity was observed in the presence of very long-chain FFAs (C20-C22), whereas polyunsaturated FFAs were not toxic. Long-chain FFAs increased peroxisomal hydrogen peroxide generation slightly, while very long-chain FFAs increased hydrogen peroxide generation more potently in both peroxisomes and mitochondria. The greater toxicity of very long-chain FFAs was accompanied by hydroxyl radical formation, along with cardiolipin peroxidation and ATP depletion. Intriguingly, only saturated very long-chain FFAs activated ER stress. On the other hand saturated very long-chain FFAs did not induce lipid droplet formation in contrast to long-chain FFAs and unsaturated very long-chain FFAs. The present data highlight the importance of structure-activity relationship analyses for the understanding of the mechanisms of lipotoxicity. Chain length and degree of saturation of FFAs are crucial factors for the toxicity of FFAs, with peroxisomal, mitochondrial, and ER stress representing the major pathogenic factors for induction of lipotoxicity. The results might provide a guide for the composition of a healthy beta-cell protective diet.
KW - Apoptosis
KW - Cell Line
KW - Diabetes Mellitus, Type 2/metabolism
KW - Endoplasmic Reticulum Stress
KW - Fatty Acids/chemistry
KW - Fatty Acids, Unsaturated/chemistry
KW - Humans
KW - Insulin-Secreting Cells/cytology
KW - Type 2 diabetes
KW - ER stress
KW - Fatty acid
KW - Lipotoxicity
KW - Human pancreatic beta cell
UR - http://www.scopus.com/inward/record.url?scp=85070530907&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2019.08.001
DO - 10.1016/j.bbadis.2019.08.001
M3 - Article
C2 - 31398470
VL - 1865
JO - Biochimica et biophysica acta: Molecular basis of disease
JF - Biochimica et biophysica acta: Molecular basis of disease
SN - 1879-260X
IS - 11
M1 - 165525
ER -