Sortilin and atherosclerosis

The complexity and intricacy of nature has recently been illustrated with the role of sortilin in atherosclerosis. Sortilin, a VPS10p sorting receptor initially identified in human brain tissue, suddenly gained much attention from the cardiovascular community as unbiased genome-wide association studies (GWASs) repeatedly demonstrated that single nucleotide polymorphisms (SNPs) at the 1p13.3 locus was strongly associated with the risk of coronary artery disease and myocardial infarction, as well as with the level of low-density lipoprotein (LDL)-cholesterol and the development of abdominal aortic aneurism. The 1p13.3 region harbors four genes CELSR2, PSRC1, MYBPHL and SORT1. The SORT1 gene, encoding sortilin, was soon implicated as the causative gene and studies on sortilin and atherosclerosis initially focused on the role of sortilin in hepatic lipoprotein metabolism. In a seminal paper, Musunuru et al. [1] found that one of the most strongly associated SNPs at 1p13.3 changes a binding site for the transcription factor C/EBFα and affects sortilin expression levels in human hepatocytes. However, pinpointing the underlying molecular mechanisms of sortilin has proven challenging. Kjolby et al. [2] found that sortilin binds apoB100 in the Golgi and facilitates the secretion of apoB100-, but not apoB48-containing, lipoproteins from hepatocytes, resulting in a positive relationship between hepatic sortilin expression and plasma LDL levels. Strong et al. [3] also showed binding of apoB100 to sortilin, but found that binding resulted in trafficking to lysosomes and a negative relationship between hepatic sortilin expression and plasma LDL levels. More recently, Gustafsen et al. [4] reported that sortilin facilitates PCSK9 secretion from hepatocytes, which in turn may increase LDL levels by down-regulating LDL receptors. Thus, the functional role of sortilin in hepatic lipoprotein metabolism is likely multiplex, involving several mechanisms, which dependent on the context may increase or decrease the level of circulating LDL [5]. Genetic studies in humans indicate that decreased hepatic sortilin expression is associated with an average net increase in LDL cholesterol and in the incidence of atherosclerotic cardiovascular disease [1]. In a recent study [6] we uncovered more complexity in the involvement of sortilin in atherosclerosis. Using the Apoe-/-mouse we demonstrated that sortilin also directly affects atherogenesis, independent of its regulatory role in lipoprotein metabolism. In the Apoe-/-mouse, the major defect is in the clearance of apoB48-containing lipoproteins that are normally removed by apoE-mediated binding to LRP1 or LDLR. Consequently, the vast majority of atherogenic lipoproteins in this setting are of the apoB48-containing type, which sortilin …