Molecular Mechanisms of Amylin Turnover, Misfolding and Toxicity in the Pancreas.
Molecular Mechanisms of Amylin Turnover, Misfolding and Toxicity in the Pancreas.
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DOI：
10.3390/molecules27031021
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发表时间：
2022-02-02
期刊：
影响因子：
--
通讯作者：
Jeremic AM
中科院分区：
文献类型：
--
作者：
Bhowmick DC;Kudaibergenova Z;Burnett L;Jeremic AM
淀粉样变是一种常见的病理事件，其中蛋白质自组装成错误折叠的可溶性和不可溶性分子形式，低聚物和原纤维，通常对细胞有毒。值得注意的是，易于聚集的人类胰岛淀粉样多肽（hIAPP）或胰淀素是一种与糖尿病患者胰岛β细胞死亡有关的胰腺激素。淀粉样蛋白（包括hIAPP）聚集和杀死细胞的统一机制仍存在争议。2型糖尿病（T2DM）的病理特征是人胰岛细胞外和细胞内积累有毒hIAPP物质、可溶性低聚物和不溶性原纤维，最终导致β细胞团块的损失。本文从分子生物学、生物化学和细胞生物学等方面综述了hIAPP在胰腺中的合成、转运和降解的分子机制。除了hIAPP周转，iapp -膜相互作用的动力学和机制；hIAPP体外、原位聚集及毒性研究；并讨论了血脂、胆固醇等糖尿病因子在这些过程中的调节作用。
Amyloidosis is a common pathological event in which proteins self-assemble into misfolded soluble and insoluble molecular forms, oligomers and fibrils that are often toxic to cells. Notably, aggregation-prone human islet amyloid polypeptide (hIAPP), or amylin, is a pancreatic hormone linked to islet β-cells demise in diabetics. The unifying mechanism by which amyloid proteins, including hIAPP, aggregate and kill cells is still matter of debate. The pathology of type-2 diabetes mellitus (T2DM) is characterized by extracellular and intracellular accumulation of toxic hIAPP species, soluble oligomers and insoluble fibrils in pancreatic human islets, eventually leading to loss of β-cell mass. This review focuses on molecular, biochemical and cell-biology studies exploring molecular mechanisms of hIAPP synthesis, trafficking and degradation in the pancreas. In addition to hIAPP turnover, the dynamics and the mechanisms of IAPP–membrane interactions; hIAPP aggregation and toxicity in vitro and in situ; and the regulatory role of diabetic factors, such as lipids and cholesterol, in these processes are also discussed.
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