Files and links (1)
Gillotte_Kristin_19988.47 MB
PDF Restricted Access, VIEWABLE UPON REQUEST: contact archives@drexel.edu
Dissertation
Mechanisms of high density lipoprotein-mediated cellular cholesterol efflux
Doctor of Philosophy (Ph.D.), Allegheny University of the Health Sciences
Mar 1998
DOI:
https://doi.org/10.17918/00007284
Abstract
High density lipoprotein (HDL) and its major protein component, apolipoportein (apo) A-I, have been shown to be critical for the transport of excess unesterified (free) cholesterol (FC) from peripheral cells to the liver in the process of reverse cholesterol transport. HDL is a structurally and functionally heterogeneous class of particles which includes subspecies exhibiting an enhanced ability to remove cholesterol from cells; the structural basis for this effect is not known. This dissertation project examines the influence of HDL lipid and protein modification on the ability of the particles to promote FC efflux from cells growing in culture. Aim 1 questions the influence of dietary modification of HDL PL fatty acyl chain composition on the ability of HDL particles to participate in FC efflux. Aim 2 of this project focuses on the role of apolipoprotein structure and conformation in the efflux process. Finally, Aims 3 and 4 investigate how lipid-poor HDL, or essentially lipid-free apo A-I, accesses cellular FC. Results of Aim 1 indicates that FC efflux to fully lipidated HDL species is not tightly governed by dietary fatty acyl chain modification of PL; this suggests that the influence of fatty acid-enriched diets affects steps in cholesterol transport and metabolism other than the initial efflux of cellular FC to HDL. Furthermore, as defined in experiments addressing Aim 2, this process is not affected by the deletion of specific domains of the apo A-I molecule. This work highlights the importance of the ability of this protein to stabilize HDL particles through the lipid-binding properties of its amphipathic [alpha]-helical segments. Results of Aim 3 demonstrate that lipid-free (poor) apo A-I molecule (pre-[beta]-HDL) obtain cholesterol by a membrane microsolubilization mechanism, different from the aqueous diffusion mechanism involved in FC efflux to lipidated species such as those addressed in Aims 1 and 2. The remainder of the experiments elucidate specific cellular conditions which enhance this apo A-I-mediated FC efflux and show that the lipid binding affinity of the protein is an important determinant in the efficacy of this process.
Metrics
19 Record Views
Details
- Title
- Mechanisms of high density lipoprotein-mediated cellular cholesterol efflux
- Creators
- Kristin Lydia Gillotte
- Contributors
- Sissel Lund-Katz (Advisor) - Drexel University, Allegheny University of the Health Sciences (1996-1998)Michael C. Phillips (Advisor) - Drexel University, Allegheny University of the Health Sciences (1996-1998)
- Awarding Institution
- Allegheny University of the Health Sciences
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Allegheny University of the Health Sciences; Philadelphia, Pennsylvania
- Number of pages
- xiii, 194 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry [Historical]; Allegheny University of the Health Sciences (1996-1998); School of Medicine (1996-1998)
- Other Identifier
- 991021888758204721