Lei Peng, Wu Wei-hui, Li Ren-wang, Ma Jing-wen, Yu Ye-ping, Cui Wei, Zhao Yu-fen, Li Yan-mei
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, PR China.
Biochem Biophys Res Commun. 2008 Apr 4;368(2):414-8. doi: 10.1016/j.bbrc.2008.01.103. Epub 2008 Feb 1.
The misfolding of islet amyloid polypeptide (IAPP, amylin) results in the formation of islet amyloid, which is one of the most common pathological features of type 2 diabetes (T2D). Amylin, a 37-amino-acid peptide co-secreted with insulin and apolipoprotein E (ApoE) from the beta-cells of pancreatic islets, is thought to be responsible for the reduced mass of insulin-producing beta-cells. However, neither the relationship between amylin and ApoE nor the biological consequence of amylin misfolding is known. Here we have characterized the interaction between ApoE4 and amylin in vitro. We found that ApoE4 can strongly bind to amylin, and insulin can hardly inhibit amylin-ApoE binding. We further found that amylin fibrillization can be prevented by low concentration of ApoE4 and promoted by high concentration of ApoE4. Taken together, we propose that under physiological conditions ApoE4 efficiently binds and sequesters amylin, preventing its aggregation, and in T2D the enhanced ApoE4-amylin binding leads to the critical accumulation of amylin, facilitating islet amyloid formation.
胰岛淀粉样多肽（IAPP，胰淀素）的错误折叠会导致胰岛淀粉样变的形成，这是2型糖尿病（T2D）最常见的病理特征之一。胰淀素是一种由胰岛β细胞与胰岛素和载脂蛋白E（ApoE）共同分泌的37个氨基酸的肽，被认为是导致产生胰岛素的β细胞数量减少的原因。然而，胰淀素与ApoE之间的关系以及胰淀素错误折叠的生物学后果尚不清楚。在这里，我们在体外对ApoE4与胰淀素之间的相互作用进行了表征。我们发现ApoE4能强烈结合胰淀素，而胰岛素几乎不能抑制胰淀素与ApoE的结合。我们进一步发现，低浓度的ApoE4可防止胰淀素纤维化，而高浓度的ApoE4则会促进其纤维化。综上所述，我们提出在生理条件下，ApoE4能有效结合并隔离胰淀素，防止其聚集，而在T2D中，增强的ApoE4-胰淀素结合会导致胰淀素的关键积累，促进胰岛淀粉样变的形成。
