Sortilin: A Protein Involved in Ldl Metabolism and Atherosclerosis

Genome-wide association studies (GWAS) have been used to identify novel genes and loci that contribute to lipid traits and coronary heart disease (CHD) in a causal manner. A locus on chromosome 1p13, which harbors the gene sortilin-1 (SORT1) encoding the protein sortilin is the locus in the human genome with the strongest association with low-density lipoprotein cholesterol (LDL-C) and is also one of the strongest loci associated with CHD. Homozygosity for the minor allele haplotype at 1p13 is associated with a >10 fold increase in hepatic SORT1 expression, a mean 16 mg/dL reduction in plasma LDL-C, and a 40% reduction in CHD risk. Sortilin has been extensively studied in the central nervous system, where it traffics multiple ligands from the Golgi apparatus to the lysosome and also serves as a cell surface endocytosis receptor for a variety of ligands. However, the role of sortilin in other cell types, most notably hepatocytes and macrophages, which are key regulators of lipid metabolism and atherosclerosis development, has not been well studied. Through a series of overexpression and mutagenesis studies in cells and mice, the Rader lab has previously shown that increased sortilin expression in liver reduces plasma LDL-C both by promoting the presecretory lysosomal degradation of the LDL precursor very-low density lipoprotein (VLDL) and by serving as an endocytosis receptor for LDL. The Rader lab has also shown that total body Sort1 deficiency is associated with compromised LDL clearance consistent with overexpression studies; however, it is also associated with a paradoxical reduction in VLDL secretion. Using a variety of liver specific Sort1 deficiency models, as well as reconstitution and mutagenesis studies, I showed that liver specificity is not responsible for the secretion paradox and instead demonstrated that sortilin plays a dual role in VLDL trafficking, serving as a chaperone that facilitates VLDL secretion as well as a transporter that promotes the presecretory degradation of VLDL, depending on the conditions and level of sortilin expression. Sortilin is strongly associated both with LDL-C levels and with CHD/atherosclerosis. Atherosclerotic cardiovascular disease is driven by elevated LDL-C, thus it is tempting to speculate that the strong association of the SORT1 locus with atherosclerosis is due solely to the LDL-C association. Because sortilin is expressed in macrophages, I hypothesized that macrophage sortilin might influence atherogenesis. Through careful interrogation of the role of sortilin in macrophages, I demonstrated that sortilin plays a role in the development of atherosclerosis independent of plasma LDL-C levels. Specifically, I showed that sortilin serves as an endocytosis receptor for LDL on macrophages, and this represents a physiologically important pathway by which LDL cholesterol enters macrophages and contributes to foam cell formation and atherosclerosis. This work increases our understanding of the role of hepatic and macrophage sortilin in LDL metabolism and atherogenesis, and provides insight into the relationship of the SORT1 locus with LDL-C levels and CHD risk. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Pharmacology This dissertation is available at ScholarlyCommons: http://repository.upenn.edu/edissertations/1935 First Advisor Daniel J. Rader Subject Categories Pharmacology | Physiology This dissertation is available at ScholarlyCommons: http://repository.upenn.edu/edissertations/1935 SORTILIN: A PROTEIN INVOLVED IN LDL METABOLISM AND ATHEROSCLEROSIS Kevin Patel A DISSERTATION in Pharmacology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2015 Supervisor of Dissertation ___________________ Daniel J. Rader Professor, Department of Medicine and Genetics Graduate Group Chairperson ____________________ Julie Blendy Professor, Department of Pharmacology Dissertation Committee Peter F. Davies, Professor, Department of Pathology and Laboratory Medicine Ellen Puré, Professor, Department of Biomedical Science Richard K. Assoian, Professor, Department of Pharmacology Edward A. Fisher, Professor, Department of Medicine, Pediatrics, and Cell Biology