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

• Published in: Circulation research Vol. 106; no. 10; pp. 1624 - 1634
• Main Authors: Christoffersen, Christina, Pedersen, Tanja Xenia, Gordts, Philip L.S.M, Roebroek, Anton J.M, Dahlbäck, Björn, Nielsen, Lars Bo
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 28.05.2010; Lippincott Williams & Wilkins
• Subjects: Animals; Apolipoproteins - deficiency; Apolipoproteins - genetics; Apolipoproteins - pharmacology; Apolipoproteins B - metabolism; Apolipoproteins B - pharmacology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Atherosclerosis (general aspects, experimental research); Atherosclerosis - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Cardiac and Cardiovascular Systems; Cardiology. Vascular system; Cholesterol - blood; Cholesterol, LDL - blood; Cholesterol, VLDL - blood; Clinical Medicine; Crosses, Genetic; Enzyme-Linked Immunosorbent Assay; Fundamental and applied biological sciences. Psychology; Humans; Kardiologi; Klinisk medicin; Lipoproteins, VLDL - metabolism; Medical and Health Sciences; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Knockout; Receptors, LDL - deficiency; Receptors, LDL - genetics; Triglycerides - blood; Vertebrates: cardiovascular system; apolipoprotein M; lipid metabolism; Cardiovascular disease; Lipids; Apolipoprotein; Lipoprotein; Metabolism; Vascular disease; Vertebrata; Mammalia; Atherosclerosis; Catabolism; Circulatory system
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.109.211086

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.