Lipid Droplets Direct Amyloid Assembly and β-Cell Stress through Interfacial Control of Amylin Aggregation
Islet amyloid polypeptide (IAPP, amylin) aggregation is a central pathological feature of type 2 diabetes, yet the cellular factors governing its conformational conversion remain incompletely understood. Here, we identify lipid droplets (LDs) as active modulators of amylin structure, aggregation, and {beta}-cell stress. Using artificial and native LDs, we show that amylin binds LD surfaces with high affinity and undergoes accelerated conversion into {beta}-sheet-rich conformations. LDs promote rapid nucleation while constraining fibril elongation, yielding shorter and morphologically distinct amyloid assemblies. Residue-resolved NMR mapping reveals a conserved N-terminal interaction interface, which is amplified upon removal of LD surface proteins, indicating that the LD proteome modulates peptide engagement and aggregation pathways. In {beta}-cells, lipid loading drives intracellular colocalization of amylin with LDs and reshapes transcriptional stress responses, attenuating ER stress and apoptosis while altering markers of {beta}-cell identity. Finally, systemic lipidomic profiling reveals coordinated remodeling of neutral lipid species across dysglycaemic states, linking intracellular LD dynamics with whole-body lipid metabolism. Together, our findings establish lipid droplets as dynamic scaffolds that reshape amylin aggregation pathways and associated {beta}-cell stress responses, providing a mechanistic bridge between lipid dysregulation and islet amyloidosis in diabetes. Significance StatementLipid droplets accumulate in pancreatic {beta}-cells during metabolic stress, yet their role in amylin aggregation remains unclear. Using structural, biophysical, and cellular approaches, we show that lipid droplet interfaces directly bind human amylin, reshape its aggregation pathway, and alter fibril morphology. Native lipid droplets and their associated surface proteins further modulate aggregation kinetics and peptide conformations. In {beta}-cells, lipid loading enhances amylin colocalization with lipid droplets and modifies stress and survival responses. Complementary lipidomic profiling reveals systemic remodeling of neutral lipid species across dysglycaemic states. These findings identify lipid droplets as active regulators of amyloid-associated proteostasis, linking lipid dysregulation to {beta}-cell dysfunction in type 2 diabetes.