Abstract
Previous studies suggest the hypothesis that apoE produced by adrenocortical cells modulates cellular cholesterol metabolism to enhance the storage of esterified cholesterol (EC) at the expense of cholesterol delivery to the steroidogenic pathway. In the present study, parameters of adrenal cholesterol metabolism and corticosteroid production were examined in wild type and apoE-deficient (apoe(-/-)) mice. Adrenal gland EC content and the EC/free cholesterol (FC) ratio in mice stressed by adrenocorticotropin (ACTH) treatment or saline injection were reduced in apoe(-/-) compared to apoe(+/+) mice. Relative to apoe(+/+) mice, apoE deficiency also resulted in increased levels of plasma corticosterone in the basal state, in response to acute or long-term ACTH treatment, and after a swim-induced neuroendocrine-directed stress test. Measurements of adrenal gland scavenger receptor class B, type I (SR-BI), LDL receptor, and LDL receptor related protein (LRP) levels and the activities of ACAT or HMG-CoA reductase showed no difference between genotypes. Apoe(-/-) and apoe(+/+) mice showed similar quantitative increases in LDL receptors, SR-BI, adrenal weight gain, and ACAT activities in response to ACTH, and both genotypes had similar basal plasma ACTH concentrations. These results suggest that the effects of apoE deficiency reflect events at the level of the adrenal gland and are specific to changes in cholesterol accumulation and corticosterone production. Further, these findings support the hypothesis that apoE acts to enhance adrenocortical EC accumulation and diminish corticosterone production.
Highlights
Previous studies suggest the hypothesis that Apolipoprotein E (apoE) produced by adrenocortical cells modulates cellular cholesterol metabolism to enhance the storage of esterified cholesterol (EC) at the expense of cholesterol delivery to the steroidogenic pathway
ApoeϪ/Ϫ mice subjected to long term saline or ACTH treatments showed a significant reduction in the ratio of EC/free cholesterol (FC) compared to apoeϪ/Ϫ mice in the basal state or after acute ACTH or saline treatments
The most prominent effects were observed in adrenal cholesterol content in ACTH-treated mice or mice stressed by saline injection
Summary
ApoE-deficient (apoEϪ/Ϫ) mice on a mixed C57BL/6J ϫ 129 background were kindly provided by N. Plasma was prepared for corticosterone assay and adrenal glands were removed, trimmed of adipose tissue, and frozen for subsequent cholesterol measurement. The pooled homogenate and rinse were extracted with 1.5 ml CHCl3-MeOH (1:2, v/v) for 15 min at room temperature, centrifuged for 15 min at 1,000 g, and the supernatant was removed to a new tube. Plasma was mixed with 10 vol of ethanol for 10 min at room temperature, centrifuged at 10,000 g for 10 min to remove protein, and aliquots were dried and assayed for corticosterone by radioimmunoassay (Endocrine Sciences, antiserum B3-163). Tissue preparation, staining, electron microscopy, and measurement of microvillar channels were carried out with sections from two mice. Tissue morphology was evaluated by light microscopy using toluidine blue-stained epon sections (0.5 m) of adrenal gland and liver tissue
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