CHOLESTEROL METABOLISM--ROLE OF APOA I

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from applicant's Abstract): The two aims of this
proposal are focused on the lipoprotein cholesteryl ester (CE) selective
uptake pathway. Selective uptake is a process in which CE is selectively
transferred from lipoproteins into the cell without the uptake and
degradation of the lipoprotein particle. This is a major pathway for the
uptake of lipoprotein cholesteryl ester into steroidogenic tissues (about
90% in rodents) and may also play a significant role in the liver in reverse
cholesterol transport. Although the selective uptake pathway has been known
for some 15 years, there has been little success in determining the protein
participants on the cell surface or the essential protein and lipid
components on the lipoprotein particle. This proposal is based on two
recent findings which now make it possible to evaluate important features of
both the lipoprotein particle and a putative selective uptake receptor on
the cell surface. The first finding is that steroidogenic tissues of
apoA-I-deficient mice show an almost complete failure to accumulate
cholesteryl ester, suggesting the hypothesis that apoA-I is essential for
selective uptake of HDL-CE. This hypothesis will be tested by evaluating
the ability of other apoproteins to substitute for apoA-I in vivo and by
analyzing the selective uptake activities of apoA-I containing and apoA-I
deficient HDL particles in cell culture. The second finding is that the
recently cloned scavenger receptor B1 (SR-B1) can mediate selective uptake
of HDL-CE when expressed in CHO cells. The hypothesis will be tested that
this receptor is responsible for selective uptake of HDL-CE and LDL-CE into
steroidogenic cells and the delivery of cholesterol for steroid production
by expressing a transfected SR-B1 gene in adrenal cells. The SR-B1
expressing cells will be used to evaluate the apoprotein specificity for
this process and to delineate domains of apoA-I that are important in native
HDL particles. These studies will provide new and important information
about a cellular process that is central to the normal functioning of
steroidogenic cells and that contributes to the regulation of the plasma
cholesterol concentration which is an important determinant of human health.
StatusFinished
Effective start/end date4/1/973/31/21

ASJC

  • Spectroscopy
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)
  • Cell Biology
  • Endocrinology, Diabetes and Metabolism