Patel Kevin M, Strong Alanna, Tohyama Junichiro, Jin Xueting, Morales Carlos R, Billheimer Jeffery, Millar John, Kruth Howard, Rader Daniel J
From the Department of Medicine (K.M.P., A.S., J.T., J.B., J.M., D.J.R.) and Department of Genetics (D.J.R.), Perelman School of Medicine at the University of Pennsylvania, Philadelphia; Section of Experimental Atherosclerosis, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (X.J., H.K.); and Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada (C.R.M.).
Circ Res. 2015 Feb 27;116(5):789-96. doi: 10.1161/CIRCRESAHA.116.305811. Epub 2015 Jan 15.
Noncoding gene variants at the SORT1 locus are strongly associated with low-density lipoprotein cholesterol (LDL-C) levels, as well as with coronary artery disease. SORT1 encodes a protein called sortilin, and hepatic sortilin modulates LDL metabolism by targeting apolipoprotein B-containing lipoproteins to the lysosome. Sortilin is also expressed in macrophages, but its role in macrophage uptake of LDL and in atherosclerosis independent of plasma LDL-C levels is unknown.
To determine the effect of macrophage sortilin expression on LDL uptake, foam cell formation, and atherosclerosis.
We crossed Sort1(-/-) mice onto a humanized Apobec1(-/-); hAPOB transgenic background and determined that Sort1 deficiency on this background had no effect on plasma LDL-C levels but dramatically reduced atherosclerosis in the aorta and aortic root. To test whether this effect was a result of macrophage sortilin deficiency, we transplanted Sort1(-/-);LDLR(-/-) or Sort1(+/+);LDLR(-/-) bone marrow into Ldlr(-/-) mice and observed a similar reduction in atherosclerosis in mice lacking hematopoetic sortilin without an effect on plasma LDL-C levels. In an effort to determine the mechanism by which hematopoetic sortilin deficiency reduced atherosclerosis, we found no effect of sortilin deficiency on macrophage recruitment or lipopolysaccharide-induced cytokine release in vivo. In contrast, sortilin-deficient macrophages had significantly reduced uptake of native LDL ex vivo and reduced foam cell formation in vivo, whereas sortilin overexpression in macrophages resulted in increased LDL uptake and foam cell formation.
Macrophage sortilin deficiency protects against atherosclerosis by reducing macrophage uptake of LDL. Sortilin-mediated uptake of native LDL into macrophages may be an important mechanism of foam cell formation and contributor to atherosclerosis development.
SORT1基因座的非编码基因变异与低密度脂蛋白胆固醇（LDL-C）水平以及冠状动脉疾病密切相关。SORT1编码一种名为sortilin的蛋白质，肝脏中的sortilin通过将含载脂蛋白B的脂蛋白靶向溶酶体来调节LDL代谢。Sortilin也在巨噬细胞中表达，但其在巨噬细胞摄取LDL以及在独立于血浆LDL-C水平的动脉粥样硬化中的作用尚不清楚。
确定巨噬细胞sortilin表达对LDL摄取、泡沫细胞形成和动脉粥样硬化的影响。
我们将Sort1(-/-)小鼠与人类化的Apobec1(-/-); hAPOB转基因背景小鼠杂交，发现在该背景下Sort1基因缺失对血浆LDL-C水平没有影响，但显著减少了主动脉和主动脉根部的动脉粥样硬化。为了测试这种效应是否是巨噬细胞sortilin缺乏的结果，我们将Sort1(-/-);LDLR(-/-)或Sort1(+/+);LDLR(-/-)骨髓移植到Ldlr(-/-)小鼠中，观察到缺乏造血sortilin的小鼠动脉粥样硬化也有类似程度的减轻，且对血浆LDL-C水平没有影响。为了确定造血sortilin缺乏减轻动脉粥样硬化的机制，我们发现sortilin缺乏对体内巨噬细胞募集或脂多糖诱导的细胞因子释放没有影响。相反，sortilin缺陷的巨噬细胞在体外对天然LDL的摄取显著减少，在体内泡沫细胞形成减少，而巨噬细胞中sortilin的过表达导致LDL摄取增加和泡沫细胞形成增加。
巨噬细胞sortilin缺乏通过减少巨噬细胞对LDL的摄取来预防动脉粥样硬化。Sortilin介导的天然LDL摄取到巨噬细胞中可能是泡沫细胞形成的重要机制，并促进动脉粥样硬化的发展。
