Progesterone inhibits apolipoprotein-mediated cellular lipid release: a putative mechanism for the decrease of high-density lipoprotein

In order to investigate the mechanism for female gonadal hormones to regulate the plasma high-density lipoprotein (HDL) level, the effect of 17 beta-estradiol and progestogens was examined in vitro on the assembly of HDL by free apolipoprotein A-I (apoA-I) with cellular cholesterol and phospholipid. ApoA-I generated HDL particles by removing cholesterol and phospholipid from human fibroblasts, MRC-5. While 17 beta-estradiol did not influence this reaction, progesterone suppressed the removal by apoA-I of both cholesterol and phospholipid, with the extent of the inhibition more for cholesterol than phospholipid. Three other synthetic progestogens showed the similar inhibitory effect on the cellular cholesterol release. Cellular cholesterol de novo-synthesized from mevalonolactone entered more into the acyl-esterified cholesterol compartment and less to the unesterified compartment in the presence of progesterone. On the other hand, progesterone did not influence the overall mass ratio of free and esterified cholesterol in the cell. Cell-surface cholesterol was also uninfluenced by progesterone when probed by extracellular cholesterol oxidase reaction or by diffusion-mediated cellular cholesterol release to cyclodextrin. Neither caveolin-1 nor ABCA1 expression was influenced by progesterone. Progesterone thus seems primarily to alter the specific intracellular cholesterol compartment that is related to the apoA-I-mediated HDL assembly. This mechanism might contribute to the decrease of plasma HDL by administration of progestogen in women under hormone replacement therapy.