Opposing Effects of Apolipoprotein M on Catabolism of Apolipoprotein B–Containing Lipoproteins and Atherosclerosis

Abstract

Rationale: Plasma apolipoprotein (apo)M is mainly associated with high-density lipoprotein (HDL). HDL-bound apoM is antiatherogenic in vitro. However, plasma apoM is not associated with coronary heart disease in humans, perhaps because of a positive correlation with plasma low-density lipoprotein (LDL). Objective: We explored putative links between apoM and very-low-density (VLDL)/LDL metabolism and the antiatherogenic potential of apoM in vivo. Methods and Results: Plasma apoM was increased ≈2.1 and ≈1.5 fold in mice lacking LDL receptors (Ldlr^−/−) and expressing dysfunctional LDL receptor–related protein 1 (Lrp1^n2/n2), respectively, but was unaffected in apoE-deficient (ApoE^−/−) mice. Thus, pathways controlling catabolism of VLDL and LDL affect plasma apoM. Overexpression (≈10-fold) of human apoM increased (50% to 70%) and apoM deficiency decreased (≈25%) plasma VLDL/LDL cholesterol in Ldlr^−/− mice, whereas apoM did not affect plasma VLDL/LDL in mice with intact LDL receptors. Moreover, plasma clearance of apoM-enriched VLDL/LDL was slower than that of control VLDL/LDL in mice lacking functional LDL receptors and LRP1, suggesting that apoM impairs the catabolism of VLDL/LDL that occurs independently of the LDL receptor and LRP1. ApoM overexpression decreased atherosclerosis in ApoE^−/− (60%) and cholate/cholesterol-fed wild-type mice (70%). However, in Ldlr^−/− mice the antiatherogenic effect of apoM was attenuated by its VLDL/LDL-raising effect. Conclusion: The data suggest that defect LDL receptor function leads to increased plasma apoM concentrations, which in turn, impairs the removal of VLDL/LDL from plasma. This mechanism opposes the otherwise antiatherogenic effect of apoM.