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Sortilin as a regulator of lipoprotein metabolism.

ABSTRACT: Elevated low-density lipoprotein cholesterol (LDL-C) is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) and myocardial infarction (MI). Much of the insight into LDL metabolism has been gained through the study of Mendelian disorders of lipid metabolism. Genome-wide associations studies (GWAS) are now being used to identify novel genes and loci that contribute to variations in LDL-C levels, and they have identified the SORT1 gene as an important modulator of LDL-C levels and ASCVD risk. Mechanistic studies in mice and cell culture also suggest that the SORT1 gene is an important regulator of lipoprotein metabolism; however, these studies disagree on the directionality of the effect of Sort1 expression on plasma lipids and the mechanism for the lipid changes. Here we review the identification of the SORT1 locus as a modulator of LDL-C levels and ASCVD risk and the first mechanistic studies that explore the role of Sortilin in lipid metabolism.

SUBMITTER: Strong A

PROVIDER: S-EPMC7089359 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Sortilin as a regulator of lipoprotein metabolism.

Strong Alanna A Rader Daniel J DJ

Current atherosclerosis reports 20120601 3

Elevated low-density lipoprotein cholesterol (LDL-C) is associated with increased risk of atherosclerotic cardiovascular disease (ASCVD) and myocardial infarction (MI). Much of the insight into LDL metabolism has been gained through the study of Mendelian disorders of lipid metabolism. Genome-wide associations studies (GWAS) are now being used to identify novel genes and loci that contribute to variations in LDL-C levels, and they have identified the SORT1 gene as an important modulator of LDL-C ...[more]

PMID: 22538429

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The enigmatic role of sortilin in lipoprotein metabolism.

Project description: Not available

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Phosphatidylinositol (3,4,5)-trisphosphate binds to sortilin and competes with neurotensin: Implications for very low density lipoprotein binding.

Project description:Sortilin is a multi-ligand sorting receptor that interacts with B100-containing VLDL and LDL as well as other ligands including neurotensin (NT). The current study investigates the hypothesis that phosphatidylinositol (3,4,5)-trisphosphate (PIP3) generated downstream of insulin action can directly bind to sortilin. NT binds to sortilin at a well characterized site via its carboxy terminus (C-term). Using a crystal structure of human sortilin (hsortilin), PIP3 is predicted to bind at this C-term site. Binding of PIP3 to hsortilin is demonstrated using surface plasmon resonance (SPR) flowing PIP3 nanodiscs over immobilized hsortilin. Studies were performed using SPR where dibutanoyl PIP3 is shown to compete with NT for sortilin binding. Rat VLDL and LDL were evaluated for PIP3 content immunologically using monoclonal antibodies directed against PIP3. Rat plasma VLDL contained three times more immunoreactive PIP3 than LDL per μg of protein. Because VLDL contains additional ligands that bind sortilin, to distinguish specific PIP3 binding, we used PIP3 liposomes. Liposome floatation assays were used to demonstrate PIP3 liposome binding to sortilin. Using SPR and immobilized hsortilin, the C-term NT tetrapeptide (P-Y-I-L) is shown to bind to hsortilin. A compound (cpd984) was identified with strong theoretical binding to the site on sortilin involved in NT N-terminal binding. When cpd984 is co-incubated with the tetrapeptide, the affinity of binding to sortilin is increased. Similarly, the affinity of PIP3 liposome binding increased in the presence of cpd984. Overall, results demonstrate that sortilin is a PIP3 binding protein with binding likely to occur at the C-term NT binding site. The presence of multiple ligands on B100-containing lipoproteins, VLDL and LDL, raises the interesting possibility for increased interaction with sortilin based on the presence of PIP3.

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Lipoprotein metabolism in familial hypercholesterolemia.

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Sortilin enhances secretion of apolipoprotein(a) through effects on apolipoprotein B secretion and promotes uptake of lipoprotein(a).

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Genome-wide screen identifies rs646776 near sortilin as a regulator of progranulin levels in human plasma.

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Project description:Heterozygous loss-of-function mutations in the GRN gene are a common cause of frontotemporal dementia. Such mutations lead to decreased plasma and cerebrospinal fluid levels of progranulin (PGRN), a neurotrophic factor with lysosomal functions. Sortilin is a negative regulator of extracellular PGRN levels and has shown promise as a therapeutic target for frontotemporal dementia, enabling increased extracellular PGRN levels through inhibition of sortilin-mediated PGRN degradation. Here we report the development of a high-affinity sortilin-binding affibody-peptide fusion construct capable of increasing extracellular PGRN levels in vitro. By genetic fusion of a sortilin-binding affibody generated through phage display and a peptide derived from the progranulin C-terminus, an affinity protein (A3-PGRNC15*) with 185-pM affinity for sortilin was obtained. Treating PGRN-secreting and sortilin-expressing human glioblastoma U-251 cells with the fusion protein increased extracellular PGRN levels up to 2.5-fold, with an EC50 value of 1.3 nM. Our results introduce A3-PGRNC15* as a promising new agent with therapeutic potential for the treatment of frontotemporal dementia. Furthermore, the work highlights means to increase binding affinity through synergistic contribution from two orthogonal polypeptide units.

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