Apolipoprotein E (APOE) deficient mice exhibit unexplained hypercorticosteronemia. Given that APOE is also produced locally within the adrenals, we evaluated the effect of adrenal-specific APOE... Show moreApolipoprotein E (APOE) deficient mice exhibit unexplained hypercorticosteronemia. Given that APOE is also produced locally within the adrenals, we evaluated the effect of adrenal-specific APOE deficiency on the glucocorticoid function. Hereto, one adrenal containing or lacking APOE was transplanted into adrenalectomized wild-type mice. Adrenal APOE deficiency did not impact adrenal total cholesterol levels. Importantly, the ability of the two adrenal types to produce glucocorticoids was also not different as judged from the similar plasma corticosterone levels. Adrenal mRNA expression levels of HMG-CoA reductase and the LDL receptor were decreased by respectively 72% (p < 0.01) and 65% (p = 0.07), suggesting that cholesterol acquisition pathways were inhibited to possibly compensate the lack of APOE. In support, a parallel increase in the expression level of the cholesterol accumulation-associated ER stress marker CHOP was detected (+117%; p < 0.05). In conclusion, our studies show that elimination of adrenocortical APOE production does not impact glucocorticoid output in wild-type mice. Show less
Hoekstra, M.; Ouweneel, A.B.; Nahon, J.E.; Geest, R. van der; Kröner, M.J.; Sluis, R.J. van der; Eck, M. van 2019
ObjectiveSince cholesterol is the sole precursor for glucocorticoid synthesis, it is hypothesized that genetic defects in proteins that impact the cellular cholesterol pool may underlie... Show moreObjectiveSince cholesterol is the sole precursor for glucocorticoid synthesis, it is hypothesized that genetic defects in proteins that impact the cellular cholesterol pool may underlie glucocorticoid insufficiency in humans. In the current study, we specifically focused on the cholesterol efflux mediator ATP-binding cassette transporter G1 (ABCG1) as gene candidate.MethodsThe adrenal transcriptional response to fasting stress was measured in wild-type mice to identify putative novel gene candidates. Subsequently, the adrenal glucocorticoid function was compared between ABCG1 knockout mice and wild-type controls.ResultsOvernight food deprivation induced a change in relative mRNA expression levels of cholesterol metabolism-related proteins previously linked to steroidogenesis, i.e. scavenger receptor class B type I (+149%; P < 0.001), LDL receptor (−70%; P < 0.001) and apolipoprotein E (−41%; P < 0.01). Strikingly, ABCG1 transcript levels were also markedly decreased (−61%; P < 0.05). In contrast to our hypothesis that decreasing cholesterol efflux would increase the adrenal cholesterol pool and enhance glucocorticoid output, ABCG1 knockout mice as compared to wild-type mice exhibited a reduced ability to secrete corticosterone in response to an ACTH challenge (two-way ANOVA: P < 0.001 for genotype) or fasting stress. As a result, glucocorticoid target gene expression levels in liver and hypothalamus were reduced and blood lymphocyte concentrations and spleen weights increased in ABCG1 knockout mice under fasting stress conditions. This was paralleled by a 48% reduction in adrenal cholesteryl ester stores and stimulation of adrenal NPC intracellular cholesterol transporter 2 (+37%; P < 0.05) and apolipoprotein E (+59%; P < 0.01) mRNA expression.ConclusionABCG1 deficiency is associated with mild glucocorticoid insufficiency in mice. Show less
