The onset and progression of type 2 diabetes is linked to the accumulation and aggregation of human islet amyloid polypeptide (hIAPP) in the pancreas. Amyloid oligomers and fibrils formed as a result of such aggregation exert high cytotoxicity. Although some pieces of evidence suggest that lipids could alter the rate of hIAPP aggregation, the effect of lipids on the aggregation properties of this peptide remains unclear. In this study, we investigate the effect of sphingophospholipid and anionic and zwitterionic phospholipids with different lengths of fatty acids on the aggregation of hIAPP. We found that anionic lipids drastically accelerate peptide aggregation, whereas this effect was substantially weaker for sphingophospholipid and zwitterionic phospholipid. Biophysical analysis revealed that the presence of lipids resulted in substantial differences in morphology and secondary structure of hIAPP fibrils compared to the protein aggregates grown in the lipid-free environment. We also found that zwitterionic phospholipids drastically increased cytotoxicity of hIAPP aggregates, whereas this effect was less evident for sphingophospholipid and anionic phospholipid. Our results showed that drastic differences in lipid-determined cytotoxicity of hIAPP aggregates were linked to molecular mechanisms of autophagy, exocytosis, and unfolded protein response. These findings suggest that molecular candidates that could disrupt protein–lipid interactions would allow for deceleration of the onset and progression of type 2 diabetes.

中文翻译：

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脂质决定了人胰岛多肽聚集体在体内的毒性


2 型糖尿病的发病和进展与胰岛淀粉样蛋白多肽 （hIAPP） 在胰腺中的积累和聚集有关。由于这种聚集而形成的淀粉样寡聚体和原纤维具有很高的细胞毒性。尽管一些证据表明脂质可以改变 hIAPP 的聚集速率，但脂质对这种肽的聚集特性的影响仍不清楚。在这项研究中，我们研究了鞘磷脂和不同脂肪酸长度的阴离子和两性离子磷脂对 hIAPP 聚集的影响。我们发现阴离子脂质会显著加速肽聚集，而这种影响对鞘磷脂和两性离子磷脂的作用要弱得多。生物物理分析显示，与在无脂质环境中生长的蛋白质聚集体相比，脂质的存在导致 hIAPP 原纤维的形态和二级结构存在显着差异。我们还发现，两性离子磷脂大大增加了 hIAPP 聚集体的细胞毒性，而这种影响对鞘氨磷脂和阴离子磷脂不太明显。我们的结果表明，hIAPP 聚集体脂质决定的细胞毒性的巨大差异与自噬、胞吐作用和未折叠蛋白质反应的分子机制有关。这些发现表明，可能破坏蛋白质-脂质相互作用的分子候选者将减缓 2 型糖尿病的发病和进展。