Restoring Cholesterol Efflux in Vascular Smooth Muscle Cells Transitioning into Foam Cells Through Liver X Receptor Activation

Abstract

ObjectiveMacrophage 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. Approach and ResultsCholesterol efflux induced by serum and HDL was evaluated in human and mouse VSMCs treated with the LXR agonist T090137 before and after methyl-{beta}-cyclodextrin (MBD)-cholesterol loading. Additional experiments included treatment with an acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor. Cholesterol-radiolabeled VSMCs were injected into the peritoneal cavity of mice, and RCT was assessed by measuring radiolabeled cholesterol in serum, liver, and feces over 48 hours. Serum and HDL induced cholesterol efflux at similar levels in both human and mouse VSMCs. Cholesterol efflux was significantly reduced following MBD-cholesterol loading; however, treatment with the LXR agonist significantly enhanced efflux. Radiolabeled foam-like VSMCs injected 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. Additionally, LXR activation restored RCT from MBD-cholesterol-loaded VSMCs to feces, reaching levels comparable to those of non-lipid-laden cells. Treatment with an ACAT inhibitor fully restored RCT rates in foam-like VSMCs, and the combination of the ACAT inhibitor and the LXR agonist further enhanced RCT. ConclusionsHDL-mediated cholesterol efflux is significantly impaired in VSMCs during their transition 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. HighlightsO_LILXR activation enhances cholesterol efflux in VSMCs in vitro, even after their transition into foam cells. C_LIO_LIVSMCs transitioning into foam cells exhibit reduced cholesterol transfer to HDL and feces in mice. C_LIO_LILXR agonist treatment enhances reverse cholesterol transport (RCT) from VSMCs to feces in vivo. C_LIO_LISelective ACAT inhibition restores RCT in foam-like VSMCs, with further enhancement observed upon LXR activation. C_LI