Opposing effects of apolipoprotein m on catabolism of apolipoprotein B-containing lipoproteins and atherosclerosis

TY - JOUR

T1 - Opposing effects of apolipoprotein m on catabolism of apolipoprotein B-containing lipoproteins and atherosclerosis

AU - Christoffersen, Christina

AU - Pedersen, Tanja Xenia

AU - Gordts, Philip L S M

AU - Roebroek, Anton J M

AU - Dahlbäck, Björn

AU - Nielsen, Lars Bo

PY - 2010/5/28

Y1 - 2010/5/28

N2 - 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), 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.

AB - 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), 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.

U2 - 10.1161/circresaha.109.211086

DO - 10.1161/circresaha.109.211086

M3 - Journal article

C2 - 20360257

SN - 0009-7330

VL - 106

SP - 1624

EP - 1634

JO - Circulation Research

JF - Circulation Research

IS - 10

ER -