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Journal of Lipid Research, Vol 35, 1200-1210, Copyright © 1994 by Lipid Research, Inc.
ARTICLES |
X Wu, N Sakata, J Dixon and HN Ginsberg
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
Previous studies have suggested that oleic acid (OA), by increasing availability of triglyceride (TG) and/or cholesteryl ester (CE), increases the secretion of apolipoprotein B (apoB) from HepG2 cells. The present studies were conducted to determine the effect of exogenous very low density lipoproteins (VLDL), which can provide TG and cholesterol to cells and be returned to the liver after secretion, in the regulation of hepatic apoB secretion. Addition of exogenous VLDL (50 micrograms protein/ml) to culture media was found to significantly stimulate apoB secretion from HepG2 cells. This effect was observed consistently with VLDL isolated from either normal or hyperlipidemic subjects. The effects of addition of VLDL were compared to that of OA, which was previously shown to stimulate apoB secretion by a posttranslational mechanism. VLDL appeared to increase apoB secretion by two mechanisms; the dominant one being posttranslational. Thus, VLDL protected newly synthesized apoB from rapid intracellular degradation in a manner similar to OA. Although treatment with VLDL increased the mass of both TG and CE, 3-fold and 2.6-fold, respectively, it appeared that the increase in TG was the critical factor associated with increased apoB secretion. Triacsin D, which is a potent inhibitor of TG synthesis, significantly inhibited the VLDL-induced stimulation of apoB secretion. Inhibition of apoB secretion by Triacsin D was associated with the loss of the protective effect of VLDL on newly synthesized apoB. In addition to its posttranslational effects, exogenous VLDL also regulated apoB secretion at the pretranslational level. Thus, we also observed that VLDL treatment consistently increased synthesis of apoB protein by 20-30%, an effect that is not observed after treatment of HepG2 cells with OA. A sensitive solution hybridization/RNase protection assay indicated that the increased apoB synthesis was associated with a 20-30% increase in apoB mRNA in VLDL-treated HepG2 cells. OA treatment had no effect on apoB mRNA levels. We conclude that VLDL treatment stimulates apoB secretion in HepG2 cells primarily by supplying fatty acids for TG synthesis. However, 20-30% of the stimulatory effect was due to a second mechanism that appeared to be pretranslational. Based on studies with OA, it appears that some component of VLDL other than TG-derived fatty acid was responsible for this effect.
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