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 -