Fibrillation of human islet amyloid polypeptide and its toxicity to pancreatic β-cells under lipid environment

• Published in: Biochimica et biophysica acta. General subjects Vol. 1864; no. 1; p. 129422
• Main Authors: Gao, Li-Ping, Chen, Hai-Chao, Ma, Ze-lin, Chen, An-Di, Du, Hong-Li, Yin, Jie, Jing, Yu-Hong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2020
• Subjects: amyloid; apoptosis; cell membranes; circular dichroism spectroscopy; death; endoplasmic reticulum; Endoplasmic reticulum stress; fibrosis; fluorescence; free fatty acids; Human islet amyloid polypeptide conformation; humans; islets of Langerhans; Lipid condition; palmitic acid; Pancreatic islet β cells; phospholipids; plasmids; polypeptides; signal transduction; toxicity; Pancreatic islet β cells; Lipid condition; Human islet amyloid polypeptide conformation; Endoplasmic reticulum stress
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2019.129422

Previous studies suggested that fibrillar human IAPP (hIAPP) is more likely to deposit in β-cells, resulting in β-cell injury. However, the changes in the conformation of hIAPP in lipid environment and the mechanism involved in β-cell damage are unclear. Synthetic hIAPP was incubated with five types of free fatty acids and phospholipids 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine (POPS), which constitute the cell membrane. Thioflavin-T fluorescence assay was conducted to analyze the degree of hIAPP fibrosis, and circular dichroism spectroscopy was performed to detect the β-fold formation of hIAPP. Furthermore, INS-1 cells were infected with human IAPP delivered by a GV230-EGFP plasmid. The effects of endogenous hIAPP overexpression induced by sodium palmitate on the survival, endoplasmic reticulum (ER) stress, and apoptosis of INS-1 cells were evaluated. The five types of free fatty acids can accelerate the fibrosis of hIAPP. Sodium palmitate also maintained the stability of fibrillar hIAPP. POPS, not POPC, accelerated hIAPP fibrosis. Treatment of INS-1 cells with sodium palmitate increased the expression of hIAPP, activated ER stress and ER stress-dependent apoptosis signaling pathways, and increased the apoptotic rate. Free fatty acids and anionic phospholipid can promote β-fold formation and fibrosis in hIAPP. High lipid induced the overexpression of hIAPP and aggravated ER stress and apoptosis in INS-1 cells, which caused β-cell death in high lipid environment. Our study reveals free fatty acids and hIAPP synergistically implicated in endoplasmic reticulum stress and apoptosis of islet β-cells. •FFAs, including PA, OA, LA, SA, and MA, can promote the fibrillation of hIAPP in vitro.•The stability of hIAPP fibrillation induced by PA was better than that of other FFAs.•the high expression of hIAPP in INS-1 cells increased the sensitivity to•lipotoxicity.•ER stress and apoptotic signals can be initiated after treatment with lipids in INS-1 cells with a high expression of hIAPP.