A lipid droplet–targeted aiegen probe reveals stage-dependent LRP1 spatial regulation and impaired amyloid-β uptake in NAFLD

Reliable visualization of lipid droplet (LD) remodeling remains challenging because conventional LD probes often suffer from background fluorescence and limited photostability in lipid-rich cellular environments. Here, we developed LD-TTP, an LD-targeting fluorescent probe integrating aggregation-induced emission (AIE) and intramolecular charge transfer (ICT) properties. LD-TTP exhibits strong fluorescence activation, high selectivity, and excellent photostability, enabling robust imaging and quantitative analysis of LD dynamics in cell-based steatotic models. Using staged steatotic HepG2 cells, we found that LD remodeling was accompanied by stage-dependent changes in the spatial distribution of the amyloid-β (Aβ)-associated receptor low-density lipoprotein receptor–related protein 1 (LRP1). In early steatosis, LRP1 expression increased and became enriched around LDs, coinciding with enhanced uptake of exogenous Cy5-labeled Aβ. As steatosis progressed, LRP1 expression declined, and its LD-associated localization was lost, paralleling reduced Aβ uptake. A diacylglycerol acyltransferase 1 (DGAT1) inhibitor partially restored Aβ uptake in moderate-to-severe steatotic HepG2 cells. These findings provide cellular-level evidence for a stage-dependent relationship among LD remodeling, LRP1 alteration, and Aβ uptake in hepatocytes. Although the present results offer mechanistic clues at the cellular level, they do not fully capture the influence of the physiological microenvironment in vivo . Further animal studies will be required to determine whether these LD–LRP1–Aβ-associated changes are maintained under physiological conditions.