Role of sortilin in lipid metabolism

Sortilin, encoded SORT1 gene at chromosome 1p13.3, is a multiligand receptor that traffics protein from the Golgi to the endosomes, secretory vesicles, and the cell surface. Genome-wide association studies (GWAS) revealed an association between sortilin and reduced plasma LDL-cholesterol (LDL-C) as well as reduced coronary artery disease (CAD). This review explores the various lipid metabolism pathways that are affected by alterations in sortilin expression.

The effects of increased hepatic sortilin on plasma LDL-C levels are mediated by increased clearance of LDL-C and decreased very LDL (VLDL) secretion because of increased autophagy-mediated lysosomal degradation of apolipoproteinB100. Sort1 knockout models have shown opposite VLDL secretion phenotypes as well as whole body lipid metabolism in response to diet challenges, leading to confusion about the true role of sortilin in the liver and other tissues.

The regulation of VLDL secretion by hepatic sortilin is complex and remains incompletely understood. Further investigation to determine the specific conditions under which both hepatic sortilin and total body sortilin cause changes in lipid metabolism pathways is needed.