Degradable Nanoparticles Restore Lysosomal pH and Autophagic Flux in Lipotoxic Pancreatic Beta Cells

Abstract

Chronic exposure to high levels of fatty acids (lipotoxicity) in pancreatic beta cells (β-cells) decreases lysosomal acidity and inhibits autophagic flux. Today, there are a lack of approaches to modify lysosomal acidity to determine whether impaired lysosomal acidification is causally inhibiting autophagic flux and cellular functions. Biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) with diameters of ≈100 nm localize to lysosomes and serve as an ideal method to deliver lactic and glycolic acid to lysosomes upon NP polymer degradation. In this study, the ability of PLGA NPs to lower lysosomal pH and restore autophagic flux is investigated in pancreatic insulin secreting (INS1) β-cells. PLGA NPs display a concentration dependent performance with higher concentrations of PLGA NPs, lowering lysosomal pH, as well as restoring autophagic flux and insulin secretion in pancreatic β-cells. These results document that acidifying the lysosome, via an external perturbation, in lipotoxic pancreatic β-cells affords a specific biological outcome of improved cellular degradative activity.

Keywords: PLGA nanoparticles; autophagic flux; insulin secretion; lipotoxicity; lysosomal acidification.