Lipids determine the toxicity of human islet polypeptide aggregates in vivo.

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.