Mendelian Randomization Study Reveals That Combined Spontaneous Free Cholesterol Diffusion and Reverse Cholesterol Transport Pathways Shift from Pro-Atherogenic to Anti-Atherogenic Effects

BACKGROUNDThe atherogenic properties of lipoproteins are well-characterized, in contrast to their putative atheroprotective effects which remain underinvestigated. METHODSWe conducted this Mendelian randomization (MR) study to analyze the causal relationship between free cholesterol (FC) levels/total lipids/FC to total lipids ratio in lipoprotein subfractions and emergency coronary revascularization (for acute coronary syndromes [ACS]) (no controls excluded). RESULTSPositive causal association between the FC to total lipid ratio/FC levels in small HDL and emergency coronary revascularization (for ACS) suggest that spontaneous FC efflux from small HDL mediates pro-atherosclerotic effects independently. Replacing FC levels with the FC-to-total-lipids ratio converts LDL from pro-atherogenic to anti-atherosclerotic particles. Or reduces pro-atherogenic effects in VLDL. In contrast, applying the same replacement in HDL particles reduces their anti-atherogenic properties. The most remarkable finding is the negative causal relationship between the FC to total lipids ratio in (large LDL [P=1.88E-02, OR:0.78, 95%CI:0.64-0.96], medium LDL [P=1.76E-02, OR:0.78, 95%CI:0.64-0.96]) and emergency coronary revascularization (for ACS). This indicates that combined spontaneous FC diffusion and reverse cholesterol transport (RCT) can shift from pro-atherogenic to anti-atherogenic effects. The loss of bidirectional FC diffusion reduces the anti-atherosclerotic effect. CONCLUSIONSHDL can exhibit pro-atherosclerotic effects through spontaneously diffused FC. However, the bidirectional exchange of FC between HDL and other lipoproteins/cells--coupled with RCT and its alternative pathways--may attenuate or even reverse atherosclerosis, implying that the lack of this specific mechanism could drive proatherogenic processes. Notably, excessive cholesteryl ester (CE) production can counteract these protective mechanisms, potentially restoring a pro-atherosclerotic state.