MECHANISMS AND PATHWAYS OF CELL CHOLESTEROL TRANSPORT

Project: Research project

Project Details

Description

Atherosclerosis remains one of the major causes of morbidity and mortality
in the US. Epidemiologic studies have shown a clear relationship between
serum cholesterol levels and development and progression of
atherosclerosis. As a result, major efforts have been instituted to
reduce the serum cholesterol of individuals at risk, through lifestyle
changes or drug therapies. Presumably, if reduction of serum cholesterol
is to produce a reduction in existing atherosclerotic lesions an important
mechanism would be to enhance removal of cholesterol from sites of
accumulation, however, such mechanisms remain poorly understood. The long
term goal of this proposal is to identify specific transport pathways
involved in HDL mediated clearance of excess cholesterol from cells to
gain further understanding of the processes involved in regression or
formation of lipid laden foam cells as occur in atherosclerosis.

We hypothesize that clearance of excess cellular cholesterol is an active
process depending on stimulation by appropriate extracellular cholesterol
acceptors that promote intracellular cholesterol transport to sites
available for removal. This project aims to show that efflux of
intracellular cholesterol requires an apolipoprotein dependent pathway
mediated by active cellular processes distinct from non-specific aqueous
diffusion of cholesterol and define cellular mechanism that facilitate
transport of cholesterol from intracellular sites to sites available for
removal by extracellular cholesterol acceptors. Cultured cells will be
the experimental model to study cholesterol efflux pathways. Advantage
will be made of somatic cell mutants with known defects in vesicular
transport. Cholesterol efflux will be measured by changes in cell
cholesterol mass and radioactivity, and changes of activities regulated by
cell cholesterol levels. We will compare various extracellular
cholesterol acceptor types to establish the contribution of apolipoprotein
independent and dependent pathways for efficient cholesterol removal and
establish if a link exists between efflux of excess cholesterol and
phospholipids by the apolipoprotein dependent pathway. We will
characterize cellular cholesterol transport pathways involving the Golgi
apparatus and identify the contribution of proteins known to regulate
vesicular transport. These studies will aid in delineating the cellular
pathways involved in cholesterol transport through and out of the cell.
Understanding these mechanisms will give greater knowledge of the
atherosclerotic process and HDL function, and will lend insights into
potential targets for pharmacological interventions to reduce the
cholesterol contents of cells.
StatusFinished
Effective start/end date8/1/967/31/01

Funding

  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute

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