Restoring cholesterol efflux in vascular smooth muscle cells transitioning into foam cells through Liver X receptor activation

Macrophage foam cells derived from vascular smooth muscle cells (VSMCs) account for 30-70 % of foam cells in atherosclerotic lesions. Liver X receptor (LXR) agonists promote high-density lipoprotein (HDL)-mediated cholesterol efflux from macrophages. This study aimed to investigate the effects of LXR activation on the reverse cholesterol transport (RCT) rate from VSMCs to feces in vivo. Both human and mouse VSMCs exhibited similar levels of cholesterol efflux when exposed to serum and HDL. However, cholesterol efflux was significantly reduced following methyl-β-cyclodextrin (MBD)-cholesterol loading, while treatment with the LXR agonist T090137 markedly enhanced efflux. Radiolabeled foam-like VSMCs injected intraperitoneally into mice exhibited impaired cholesterol transfer to serum, HDL, and feces compared to non-lipid-laden VSMCs. Pre-treatment with the LXR agonist increased radiolabeled cholesterol levels in serum and HDL and doubled its fecal excretion. Furthermore, LXR activation restored RCT from MBD-cholesterol-loaded VSMCs to feces, reaching levels comparable to those of non-lipid-laden cells. Treatment with an acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor fully restored RCT rates in foam-like VSMCs, and the combination of the ACAT inhibitor and the LXR agonist further enhanced RCT. These findings indicate that HDL-mediated cholesterol efflux is significantly impaired during the transition of VSMCs into foam cells. Pharmacological activation of LXR enhances RCT from VSMCs to feces in vivo and restores the impaired RCT from transitioning VSMCs. The combination of LXR agonists and ACAT inhibitors holds promise as a synergistic therapeutic approach to restoring cholesterol homeostasis in lipid-laden VSMCs, offering potential strategies to mitigate atherosclerosis.