Human apoE is present on nearly all serum lipoproteins and plays a protective role in atherosclerosis by acting both as a ligand for receptor-mediated lipoprotein clearance and as an acceptor for cholesterol exported by peripheral cells

Journal of Lipid Research Volume 55, 2014 2073 Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc. Human apoE is present on nearly all serum lipoproteins and plays a protective role in atherosclerosis by acting both as a ligand for receptor-mediated lipoprotein clearance and as an acceptor for cholesterol exported by peripheral cells ( 1, 2 ). apoE on triglyceride-rich lipoproteins binds to the LDL receptor (LDLR), the LDLR-related protein 1 (LRP1), and heparan sulfate proteoglycans (HSPGs) ( 3, 4 ). Common polymorphisms of human apoE (apoE2, -E3, and -E4) infl uence lipid metabolism due to differences in receptor binding activity and lipoprotein association preference ( 5–9 ). About 90% of serum apoE is made in the liver ( 10 ) and the remainder is produced by macrophages ( 11 ). apoE made by macrophages is secreted into the circulation, where it associates with lipoproteins and mediates their hepatic uptake by the liver ( 3, 6 ). The atheroprotective role of macrophage apoE has been well documented, with macrophage-derived apoE being shown to protect against atherosclerosis during both early ( 12, 13 ) and late plaque development ( 11 ); protection remains even when it is expressed in low amounts ( 14 ) and in the absence of changes in serum lipid levels ( 15 ). Macrophage apoE expression can alter lesion composition by modifying the recruitment of infl ammatory monocytes (Ly6C/ CCR2-positive cells) (16–18), and also at a later stage, can change the macrophage composition from anti-infl ammatory M2 (arginase I-positive cells) to pro-infl ammatory M2 (arginase II-positive cells ) ( 19 ). Lipoprotein glomerulopathy (LPG) is a rare but severe renal disease characterized by accumulation of lipoproteins in Abstract Lipoprotein glomerulopathy (LPG) is a renal disease often accompanied by dyslipidemia and increased serum apoE levels. apoE Sendai (Arg145Pro), a rare mutant based on the apoE3 sequence carrying an apoE2 charge, causes LPG in humans and transgenic mice, but its effects on the artery wall are unknown. Macrophage expression of apoE Sendai may also directly infl uence renal and arterial homeostasis. We investigated the effects of macrophageexpressed apoE Sendai in apoE / mice with or without LDL receptor (LDLR). Murine bone marrow transduced to express apoE2, apoE3, or apoE Sendai was transplanted into lethally irradiated mice. Macrophage apoE Sendai expression reduced aortic lesion size and infl ammation by 32 and 28%, respectively, compared with apoE2 in apoE / recipients. No differences in lesion size or infl ammation were found between apoE Sendai and apoE3 in apoE / recipients. Macrophage apoE Sendai expression also reduced aortic lesion size by 18% and infl ammation by 29% compared with apoE2 in apoE / /LDLR / recipients. Glomerular lesions compatible with LPG with increased mesangial matrix, extracellular lipid accumulation, and focal mesangiolysis were only observed in apoE / /LDLR / mice expressing apoE Sendai . Thus, macrophage expression of apoE Sendai protects against atherosclerosis while causing lipoprotein glomerulopathy. This is the fi rst demonstration of an apoprotein variant having opposing effects on vascular and renal homeostasis. —Tavori, H., D. Fan, I. Giunzioni, L. Zhu, M. F. Linton, A. B. Fogo, and S. Fazio. Macrophage-derived apoE Sendai suppresses atherosclerosis while causing lipoprotein glomerulopathy in hyperlipidemic mice. J. Lipid Res. 2014. 55: 2073–2081.