Activation of the Reverse Cholesterol Transport Pathway: A Strategy to Ameliorate Lipid Metabolic Dyshomeostasis in the Microenvironment Following Spinal Cord Injury

Spinal cord injury (SCI) causes massive release of myelin‑derived lipids, driving macrophage‑to‑foam‑cell transformation that sustains inflammation and impedes repair. Although reverse Cholesterol transport (RCT) mediates lipid efflux, its functional dynamics within the SCI microenvironment remain unclear. Using a mouse T10 contusion model, we examined key RCT components (ABCA1, ABCG1, and apoE) by qRT‑PCR, Western blot, and immunofluorescence. We also evaluated the LXR Agonist AZ876 for its capacity to modulate RCT and promote functional recovery. We observed a pronounced imbalance in RCT after SCI. ABCA1 and apoE were persistently upregulated, but ABCA1 localized predominantly to astrocytes rather than macrophages. Notably, ABCG1 protein levels declined progressively despite increased mRNA expression, indicating a post‑transcriptional bottleneck that favors foam‑cell accumulation. AZ876 activated the LXR/RXR axis and induced long‑term transcriptomic remodeling of lipid metabolism. Early AZ876 treatment increased ABCA1 and partially restored ABCG1 protein expression, markedly reducing Oil Red O-positive foam‑cell accumulation at the lesion site. These microenvironmental improvements were associated with decreased TNF‑α levels and enhanced locomotor recovery, as evidenced by improved BMS scores and open‑field performance. The lipid-rich environment after spinal cord injury rapidly activates the initial steps of RCT, but a pronounced post-transcriptional suppression of ABCG1 impedes downstream RCT processes. Although the LXR Agonist AZ876 partially overcomes this bottleneck and improves neurological outcomes, it fails to fully restore ABCG1 protein levels, indicating that transcriptional activation alone is insufficient. Future strategies should target the mechanisms of ABCG1 protein instability to fully correct lipid metabolic dysregulation.