Institute of Experimental Diabetes Research, Hannover Medical School, Hannover, Germany; Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
Biochim Biophys Acta Mol Basis Dis. 2019 Nov 1;1865(11):165525. doi: 10.1016/j.bbadis.2019.08.001. Epub 2019 Aug 6.
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.
脂毒性被认为是 2 型糖尿病中β细胞功能障碍的主要原因。然而，其潜在机制尚不清楚。为了更好地了解毒性，我们分析了多种结构不同的游离脂肪酸（FFAs）在人 EndoC-βH1 β细胞中的作用。将人 EndoC-βH1 β细胞暴露于生理饱和和单不饱和长链 FFAs 中会诱导细胞凋亡。值得注意的是，饱和 FFAs 的链长增加比不饱和 FFAs 更快地导致毒性增加。在存在非常长链 FFAs（C20-C22）的情况下观察到最高的毒性，而多不饱和 FFAs 没有毒性。长链 FFAs 略微增加过氧化物酶体中过氧化氢的生成，而非常长链 FFAs 更有效地增加过氧化物酶体和线粒体中过氧化氢的生成。非常长链 FFAs 的更高毒性伴随着羟基自由基的形成，以及心磷脂过氧化和 ATP 耗竭。有趣的是，只有饱和的非常长链 FFAs 激活了内质网应激。另一方面，与长链 FFAs 和不饱和非常长链 FFAs 相反，饱和的非常长链 FFAs 不会诱导脂滴形成。目前的数据强调了结构-活性关系分析对于理解脂毒性机制的重要性。FFAs 的链长和饱和度是 FFAs 毒性的关键因素，过氧化物酶体、线粒体和内质网应激是诱导脂毒性的主要致病因素。这些结果可能为健康的β细胞保护饮食的组成提供指导。
