Sortilin as a novel regulator of plasma cholesterol, very-low density lipoprotein secretion and LDL catabolism

Elevated low-density lipoprotein cholesterol (LDL-C) is associated with increased risk of cardiovascular disease. Genome-wide association studies (GWAS) have identified a variant at a locus on chromosome 1p13 harboring the gene SORT1, which encodes the protein sortilin, as very strongly associated with a greater than 10-fold increase in hepatic expression of SORT1, reduced plasma levels of LDL-C, and reduced risk of myocardial infarction (MI). Through a series of overexpression, knockout and knockdown studies we have interrogated a role for Sort1 in lipid metabolism, and found that increased hepatic Sort1 expression is associated with reduced plasma cholesterol, reduced secretion of the LDL precursor very-low density lipoprotein (VLDL), and increased LDL catabolism. We further demonstrate that increased Sort1 expression reduces VLDL secretion and promotes LDL catabolism by directly binding to VLDL/LDL particles and directing them to the endolysosomal system for degradation. We also show by using liver specific Sort1 small-interfering RNAs (siRNAs) that reductions in Sort1 expression in mouse liver increases plasma cholesterol, while total body Sort1 deficiency either does not affect plasma cholesterol or leads to a paradoxical reduction in plasma cholesterol. Loss-of-function studies demonstrate that sortilin serves as a bona fide receptor for LDL, but is also associated with reduced VLDL secretion. We thus provide functional evidence that genetically-increased hepatic sortilin both reduces hepatic VLDL secretion and increases LDL catabolism, providing dual mechanisms for the very strong association between increased hepatic sortilin expression and reduced plasma LDL-C levels in humans.