Abstract
Cholesterol was poorly available to free apolipoprotein (apo)A-I-mediated cellular lipid efflux from cholesterol-loaded rat vascular smooth muscle cells generating cholesterol-poorer pre-beta-HDL particles than those generated from macrophages by the same reaction (Li, Q., Komaba, A., and Yokoyama, S. (1993) Biochemistry 32, 4597-4603). The factors known to induce transformation of the smooth muscle cells into a macrophage-like stage were used in order to modulate this reaction, such as human platelet-derived growth factor, macrophage colony-stimulating factor, and phorbol 12-myristate-13-acetate (PMA). When the cells were stimulated by PMA following the pretreatment with platelet-derived growth factor plus macrophage colony-stimulating factor, cholesterol efflux mediated by free apoA-I increased 3-fold without changing phospholipid efflux, resulting in generation of pre-beta-HDL particles more rich in cholesterol. This treatment had only a little or no effect on apparent cellular cholesterol efflux to HDL or lipid microemulsion, respectively. Overall cellular free cholesterol pool size was unaffected by the treatment, and probing by extracellular cholesterol oxidase did not detect gross change in the cellular surface cholesterol. This specific enrichment of cholesterol in the apoA-I-mediated cellular lipid efflux was reversed by protein kinase C inhibitors. Measurement of intracellular cholesterol esterification suggested that PMA induced translocation of intracellular cholesterol to a specific pool for apoA-I-mediated efflux, and a protein kinase C inhibitor reversed this effect.
Highlights
When cholesterol is transported from the peripheral cells to the liver for its biological degradation, the first step of the pathway is efflux of cellular cholesterol to plasma lipoproteins
We demonstrated that lipid-free apolipoproteins having multisegments of amphiphilic helix mediate the net efflux of cholesterol and phospholipid from various types of cells, generating new High density lipoprotein (HDL)-like particles with these cellular lipids (Hara and Yokoyama, 1991, 1992; Hara et al, 1992; Komaba et al, 1992)
Other groups have reported similar data using lipid-free apolipoproteins (Bielicki et al, 1992; Forte et al, 1993). These results may explain why cellular cholesterol appears in pre--HDL fraction in the very early stage of the efflux (Castro and Fielding, 1988; Miida et al, 1990, 1992); pre--HDL particles are newly generated with cellular lipid by apolipoproteins dissociated from HDL, rather than the particles in the medium preferably “accepting” cholesterol from cellular surface
Summary
When cholesterol is transported from the peripheral cells to the liver for its biological degradation, the first step of the pathway is efflux of cellular cholesterol to plasma lipoproteins. Other groups have reported similar data using lipid-free apolipoproteins (Bielicki et al, 1992; Forte et al, 1993) These results may explain why cellular cholesterol appears in pre--HDL fraction in the very early stage of the efflux (Castro and Fielding, 1988; Miida et al, 1990, 1992); pre--HDL particles are newly generated with cellular lipid by apolipoproteins dissociated from HDL, rather than the particles in the medium preferably “accepting” cholesterol from cellular surface. Free apolipoprotein-mediated cellular cholesterol efflux seems to be a distinct pathway from nonspecific physicochemical cholesterol exchange reaction between cellular surface and lipoproteins. This may lead us to the hypothesis that HDL-mediated lipid efflux includes two distinct mechanisms. The maximum contribution of the free apolipoprotein-mediated portion could be as much as 40% of apparent HDL-mediated efflux (Komaba et al, 1992; Francis et al, 1995)
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