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Sortilin as a novel regulator of plasma cholesterol, very-low density lipoprotein secretion and LDL catabolism.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Strong, Alanna.
- Language:
- English
- Subjects (All):
- Molecular biology.
- Biology, Molecular.
- 0307.
- Penn dissertations--Cell and molecular biology.
- Cell and molecular biology--Penn dissertations.
- Local Subjects:
- Biology, Molecular.
- Penn dissertations--Cell and molecular biology.
- Cell and molecular biology--Penn dissertations.
- 0307.
- Physical Description:
- 172 pages
- Contained In:
- Dissertation Abstracts International 74-06B(E).
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- 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.
- Notes:
- Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2012.
- Source: Dissertation Abstracts International, Volume: 74-06(E), Section: B.
- Advisers: Daniel J. Rader; Meera V. Sundaram.
- Local Notes:
- School code: 0175.
- ISBN:
- 9781267898654
- Access Restriction:
- Restricted for use by site license.
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