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J. Biol. Chem., Vol. 268, Issue 31, 22967-22970, Nov, 1993
N Sakata, X Wu, JL Dixon and HN Ginsberg
Under lipid-poor conditions, most newly synthesized apolipoprotein B100
(apoB) undergoes rapid degradation in Hep G2 cells such that only a small
fraction of newly synthesized apoB is actually secreted. Addition of oleate
to Hep G2 culture medium stimulates apoB secretion by a post- translational
mechanism. In the current studies we have explored oleate- stimulation of
apoB secretion by using calpain inhibitor I, N-acetyl-
leucyl-leucyl-norleucinal (ALLN), a compound that inhibits the
intracellular degradation of 3-hydroxy-3-methylglutaryl-coenzyme A
reductase and the T cell receptor alpha subunit. Preincubation of Hep G2
cells with ALLN (40 micrograms/ml) for 1 h markedly inhibited degradation
of newly synthesized apoB. Whereas only 32% of newly labeled apoB remained
intact (cells+medium) in control cells after a 10- min pulse with
[3H]leucine followed by a 60-min chase, 84% of labeled apoB was intact in
ALLN-treated cells. However, most of the ALLN- protected apoB remained
intracellular, as ALLN did not stimulate the rate of apoB secretion over
the control rate (12 versus 9.2%). Although secretion of apoB was not
accelerated, the protection afforded by ALLN continued for several hours,
and labeled apoB continued to be secreted over 3 h of chase after which
secretion ceased. The protection afforded by ALLN resulted in 37% of
labeled apoB secreted by 3 h compared to 15% in control cells. In contrast,
simultaneous treatment of cells with ALLN and oleate both accelerated and
increased total apoB secretion, such that 36% of initially labeled apoB was
recovered in the medium by 60 min and 71% of labeled apoB was secreted by
180 min of chase. These data show that ALLN and oleate affect apoB
metabolism by different mechanisms. Although ALLN can protect nascent apoB
from rapid early intracellular degradation, it does not accelerate apoB
secretion. In contrast, although our results can not rule out the
possibility that oleate may directly inhibit proteolysis of apoB, oleate
appears to protect apoB mainly by facilitating transport of apoB out of a
protease- containing compartment associated with the endoplasmic reticulum.
Proteolysis and lipid-facilitated translocation are distinct but competitive processes that regulate secretion of apolipoprotein B in Hep G2 cells
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
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