Sortilin and lipoprotein metabolism: making sense out of complexity

Genome-wide association studies have been used as an unbiased tool to identify novel genes that contribute to variations in LDL cholesterol levels in the hopes of uncovering new biology and new therapeutic targets for the treatment of atherosclerotic cardiovascular disease. The locus identified by genome-wide association studies with the strongest association with LDL cholesterol and atherosclerotic cardiovascular disease is the 1p13 sortilin-1 (SORT1) locus. Here, we review the identification and characterization of this locus, the initial physiological studies describing the role of SORT1 in lipoprotein metabolism, and recent work that has begun to sort out the complexity of this role.

Studies by several groups support an important role for sortilin in lipoprotein metabolism; however, the directionality of the effect of sortilin on plasma cholesterol and its role in the secretion of hepatic lipoproteins remains controversial. Studies by several groups support a role for sortilin in inhibiting lipoprotein export, whereas other studies suggest that sortilin facilitates lipoprotein export.

Understanding the mechanism by which sortilin affects LDL cholesterol will increase our understanding of the regulation of lipoprotein metabolism and hepatic lipoprotein export and may also allow us to harness the power of the 1p13 SORT1 locus for the treatment of atherosclerotic cardiovascular disease.