Targeted inhibition of ATP‐binding cassette transporter A1 protein degradation promotes reverse cholesterol transport and reduces atherosclerosis in mice (832.15)

Objective ATP‐Bing Cassette Transporter A1 (ABCA1) is a key protein in the rate‐limiting step of reverse cholesterol transport, which maintains plasma HDL levels. Transcriptional regulating ABCA1 promotes HDL generation and RCT is well established, however, little is known about the posttranspcriptional inhibition of ABCA1 degradation on macrophage RCT and atherosclerosis. We therefore investigate whether suppressing ABCA1 degradation would promote RCT and reduce atherosclerosis. Methods and results Pulse‐chase analysis revealed that a small molecular (IMM‐H007) significantly inhibits ABCA1 degradation and facilitates its cell‐surface localization in THP‐1 macrophages. In vitro tests described that IMM‐H007 promote cholesterol efflux via ABCA1‐mediated pathway. Animals fed a western diet containing 1.25% cholesterol with IMM‐H007 treatment showed an increase in circulating HDL levels and enhanced RCT to the plasma, liver, and feces. Additional, elevated hepatic ABCA1 expression and functional HDL were also observed in mice after IMM‐H007 administration. Furthermore, suppressing ABCA1 degradation gave rise to the reduction of plaque size, lipid content and increase markers of plaque stability in apoE‐/‐ mice. Conclusion Our findings reveal that raising HDL levels by inhibiting ABCA1 protein degradation enhances reverse cholesterol transport and decreases plaque formation, suggesting that it is a promising HDL therapeutic strategy to protect against atherosclerotic. IMM‐H007 could be a leading compound for development of drugs for raising HDL quantity and function.