REGULATION OF THE SECRETION OF APOB-LIPOPROTEINS

Project Details

Description

Increased concentrations of plasma cholesterol, LDL cholesterol, and LDL
apo B have been implicated as risk factors for the development of
atherosclerosis. The levels of LDL in plasma will be significantly
regulated by LDL receptor activity, especially hepatic LDL receptor
activity. However, LDL concentrations are also influenced by the rates of
VLDL secretion and conversion to LDL. In the last several years it has
become evident, that overproduction of apo B-containing particles, without
an accompanying comparable increase in their fractional catabolic rate, is
responsible for a large percentage of patients with hypercholesterolemia.
Therefore, the proposed studies will investigate the regulation of apo B
secretion in human hepatoma cells (Hep G2) and, later, in cultures of
primary human hepatocytes.

A study recently completed in my laboratory has shown that only a fraction
of the apo B molecules synthesized by Hep G2 cells are secreted, in fact,
a large proportion are rapidly degraded soon after synthesis. In addition,
adding oleic acid to the culture medium had the effect of protecting
nascent apo B from intracellular degradation. Thus, it appears that a
post-translational mechanism is responsible for determining the number of
apo B molecules secreted by the hepatocyte. It is the PI's overall
hypothesis that the secretion of apo B-containing lipoproteins is regulated
by processes which direct apo B to either the degradative or secretory
pathways. It will be important in the understanding of the regulation of
apo B secretion to define this pathway in more detail and study what
factors affect it.

Therefore, the specific aims of this proposal are: 1) Delineate the post-
translational mechanism which regulates the proportion of newly synthesized
apo B that is secreted by Hep G2 cells. 2) Determine how oleic acid alters
the above degradative mechanism and protects nascent apo B from
intracellular degradation. 3) Determine whether changes in cellular
cholesterol availability affect the apo B degradative mechanism. 4)
Determine which domains of the apo B molecule are involved in the
regulation of intracellular degradation of apo B by transfecting Hep G2
cells with cDNAs coding for truncated apo B molecules.
StatusFinished
Effective start/end date9/1/928/31/96

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

ASJC

  • Cardiology and Cardiovascular Medicine

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