The LDL receptor (LDLR) is the principal endocytic receptor that removes both LDL and its lipoprotein precursor, VLDL remnants, from the circulation. Defects in LDLR function elevate LDL-cholesterol levels (hypercholesterolemia), promoting atherosclerosis and early onset of coronary artery disease. The LDLR has long been viewed as a simple endocytic receptor, carrying in bound lipoprotein when the receptor undergoes constitutive endocytosis. Studies supported by the prior funded period show that the LDLR is more sophisticated in that the LDLR distinguishes between LDL and VLDL remnants during lipoprotein uptake. Preliminary data for this proposal shows that LDL and VLDL traffic differently through endosomes and that this trafficking difference allows LDL to be degraded faster than VLDL remnants. Use of different endocytic mechanisms for each lipoprotein provides the opportunity to regulate each process independently. Consistent with this possibility, our preliminary data show that S-nitrosylation of the ARH adaptor protein is required for LDL uptake, but not VLDL remnant uptake, by the LDLR. The two goals of this proposal are (i) to determine how the LDLR distinguishes between LDL and VLDL remnants during lipoprotein uptake and (ii) to determine how ARH nitrosolation regulates LDL uptake. To achieve the first goal, proposed studies will test the hypothesis that the ability of multiple LDLRs to bind individual VLDL remnants informs how the LDLR internalizes VLDL remnants. These studies will also characterize how LDL and VLDL are differentially processed in endosomes. To achieve the second goal, the proposed studies will test the hypothesis that ARH nitrosylation is necessary for targeting LDLR-LDL complexes to coated pits. Studies under the second goal will also test the hypothesis that nitric oxide regulation of ARH function controls LDL uptake in vivo.

Public Health Relevance

Our published data show that the LDL receptor (LDLR) handles LDL and VLDL differently during uptake. This proposal will characterize how the LDLR distinguishes LDL from VLDL and determine how S-nitrosylation of the ARH adaptor protein regulates the LDL uptake process.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085218-07
Application #
8399043
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
2006-08-01
Project End
2015-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
7
Fiscal Year
2013
Total Cost
$227,052
Indirect Cost
$84,252
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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