Macrophage Sortilin Promotes LDL Uptake, Foam Cell Formation, and Atherosclerosis

• DOI: 10.1161/circresaha.116.305811
• Publication Date: 2015-01-16T04:01:43Z
• Authors: Kevin M. Patel; Alanna Strong; Junichiro Tohyama; Xueting Jin; Carlos R. Morales; Jeffery Billheimer; John Millar; Howard Kruth; Daniel J. Rader
• Keywords: Foam cell; Ex vivo; Low-density lipoprotein

Rationale: Noncoding gene variants at the SORT1 locus are strongly associated with low-density lipoprotein cholesterol (LDL-C) levels, as well coronary artery disease. encodes a protein called sortilin, and hepatic sortilin modulates LDL metabolism by targeting apolipoprotein B–containing lipoproteins to lysosome. Sortilin is also expressed in macrophages, but its role macrophage uptake of atherosclerosis independent plasma LDL-C levels unknown. Objective: To determine effect expression on uptake, foam cell formation, atherosclerosis. Methods Results: We crossed Sort1 −/− mice onto humanized Apobec1 ; hAPOB transgenic background determined that deficiency this had no dramatically reduced aorta aortic root. test whether was result deficiency, we transplanted ;LDLR or +/+ bone marrow into Ldlr observed similar reduction lacking hematopoetic without an levels. In effort mechanism which atherosclerosis, found recruitment lipopolysaccharide-induced cytokine release vivo. contrast, sortilin-deficient macrophages significantly native ex vivo formation vivo, whereas overexpression resulted increased formation. Conclusions: Macrophage protects against reducing LDL. Sortilin-mediated may be important contributor development.