EFFECTS OF PROLONGED ACTH-STIMULATION ON ADRENOCORTICAL CHOLESTEROL RESERVE AND APOLIPOPROTEIN-E CONCENTRATION IN YOUNG AND AGED FISCHER-344 MALE RATS

Changes in the morphology of rat adrenal cortex with age include incre ased accumulations of lipid droplets and lipofuscin granules. Because glandular concentrations of cholesteryl esters (CE) and apolipoprotein (apo) E are also increased in parallel, the utilization or metabolism of lipid-droplet stored CE for steroidogenesis might be altered in ag ing cells. To explore this possibility, adrenocortical cholesterol sto rage and utilization were studied in 3-6 months-old (mo) (Y) rats and 20-23 mo (O) Fischer 344 male rats. Both groups received either adreno corticotropin (ACTH1-39, Acthar gel) or gelatin alone daily for seven consecutive days. We found that: (a) the CE concentration in O rats, b ut not Y animals, was diminished by ACTH. The depleted CE in stimulate d-O rats was replenished within five days post stimulation. Failure to deplete CE in stimulated-Y rats was not associated with an insufficie nt dose of the hormone, since stimulation of Y animals with higher dos es of ACTH actually increased the CE concentration. In contrast, adren ocortical free cholesterol concentration remained constant during stim ulation regardless of age. (b) The depleted CE in stimulated-O rats wa s principally comprised of cholesteryl adrenate, cholesteryl arachidon ate and cholesteryl cervonate. The accumulated CE in stimulated-Y anim als was primarily comprised of cholesteryl adrenate, cholesteryl arach idonate and cholesteryl oleate. (c) Whereas in stimulated-Y rats adren al apoE concentration declined, the concentration in stimulated O anim als was well maintained. (d) In vitro, adrenal homogenate or cytosolic fraction from stimulated-O rats displayed a higher capacity to hydrol yze exogenous CE than its Y counterpart. However, cholesterol esterifi cation with external fatty acid substrates in adrenal homogenate or mi crosomal fraction was comparable in the two age-groups. Our findings r evealed altered adrenocortical cholesterol reserve in O rats to cope w ith prolonged ACTH-stimulation. Changes in apoE levels and CE hydrolys is activity may be factors associated with this alteration. Depletion and accumulation of adrenocortical CE are reflected in parallel change s in cholesteryl adrenate and cholesteryl arachidonate, suggesting phy siologic importance of these polyunsaturated fatty acids during sustai ned steroidogenesis. (C) 1998 Elsevier Science Ltd. All rights reserve d.