© 1999 American Heart Association, Inc.
Original Contributions |
Effects of 
-Tocotrienol on ApoB Synthesis, Degradation, and Secretion in HepG2 Cells
From the Division of Medical Technology (A.T., Q.W.), University of Hawaii at Manoa, Honolulu; Palm Oil Research Institute of Malaysia (A.G.), Kuala Lumpur; and Department of Laboratory Medicine, Hospital for Sick Children, University of Toronto (K.A.), Canada.
Correspondence to A. Theriault, Division of Medical Technology, University of Hawaii at Manoa, 1960 East-West Rd, Bio C-206, Honolulu, HI 96822. E-mail andret{at}hawaii.edu
Abstract—
-Tocotrienol
(-T3), a naturally occurring analog of tocopherol
(vitamin E), has been shown to have a
hypocholesterolemic effect in animals and humans.
Unlike tocopherol, it has also been shown to reduce plasma
apoB levels in hypercholesterolemic subjects. The aim
of this study was to define the mechanism of action of -T3 on
hepatic modulation of apoB production using cultured HepG2
cells as the model system. HepG2 cells preincubated with -T3 were
initially shown to inhibit the rate of incorporation of
[14C]acetate into cholesterol in a
concentration- and time-dependent manner, with a maximum 86±3%
inhibition at 50 µmol/L observed within 6 hours. -T3, on the
other hand, had no significant effect on the uptake of
[14C]glycerol into pools of cellular
triacylglycerol and phospholipid relative to
untreated control. The rate of apoB synthesis and secretion was then
studied by an [35S]methionine pulse-labeling experiment
and quantified by immunoprecipitating apoB on chasing up to 3 hours. An
average reduction of 24±3% in labeled apoB in the media was apparent
with -T3 despite a 60±2% increase in apoB synthesis. Fractionation
of secreted apoB revealed a relatively denser lipoprotein particle,
suggesting a less stable particle. Using a
digitonin-permeabilized HepG2 cell system, the effects
of -T3 on apoB translocation and degradation in the endoplasmic
reticulum were further investigated. The generation of a specific
N-terminal 70-kDa proteolytic fragment proved to be a sensitive measure
of the rate of apoB translocation and degradation. The abundance of
this fragment increased significantly in -T3-treated cells relative
to untreated control cells (50±21%) after 2 hours of chase. In
addition, the presence of -T3 resulted in an average decrease of
64±8% in intact apoB. Taken together, the data suggest that -T3
stimulates apoB degradation possibly as the result of decreased apoB
translocation into the endoplasmic reticulum lumen. It is speculated
that the lack of cholesterol availability reduces the
number of secreted apoB-containing lipoprotein particles by limiting
translocation of apoB into the endoplasmic reticulum lumen.
Key Words: apoB • tocotrienol • tocopherol • HMG-CoA reductase inhibitor • degradation
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