The islet amyloid polypeptide (IAPP) or amylin maintains a key role in metabolism. This 37-residues-peptide could form pancreatic amyloids， which are a characteristic feature of diabetes mellitus type 2. However， some species do not form amyloid fibril structures. By employing a biomimetic approach， we generated an extensive panel of optimized sequences of IAPP， which could drastically reduce aggregation propensity. A structural and cellular characterization analysis was performed on the C-terminal domain with the highest aggregation propensity. This allowed the observation of an aggregative phenomenon dependent of the lipid environment. Evaluation of the new FR variant demonstrated inhibition of β-she... More
The islet amyloid polypeptide (IAPP) or amylin maintains a key role in metabolism. This 37-residues-peptide could form pancreatic amyloids， which are a characteristic feature of diabetes mellitus type 2. However， some species do not form amyloid fibril structures. By employing a biomimetic approach， we generated an extensive panel of optimized sequences of IAPP， which could drastically reduce aggregation propensity. A structural and cellular characterization analysis was performed on the C-terminal domain with the highest aggregation propensity. This allowed the observation of an aggregative phenomenon dependent of the lipid environment. Evaluation of the new FR variant demonstrated inhibition of β-sheet structure and， therefore， amyloid formation on the native C-terminal， phenomenon that was associated with functional optimization in calcium and cholesterol management coupled with the optimization of insulin secretion by beta cells. When FR variant was evaluated in microglia cells， a model of amyloidosis， cytotoxic conditions were not registered. In addition， it was found that C-terminal sequences of IAPP could modulate cholesterol metabolism in hepatocytes through regulation of SREBP-2， apoA-1， ABCA1， and LDLR， mechanism that may represent a new function of IAPP on the metabolism of cholesterol， increasing the LDL endocytosis in hepatocytes. Optimized sequences with only one residue modification in the C-terminal core aggregation could diminish β-sheet formation and represent a novel strategy adaptable to other pharmacological targets. Our data suggest a new IAPP function associated with rearrangements on metabolism of cholesterol in hepatocytes.
