Abstract
Background and aimsStatin treatment disrupts HMG-CoA reductase-mediated endogenous cholesterol synthesis and lowers plasma LDL-cholesterol levels. Although statin treatment can theoretically impair adrenal steroid hormone synthesis, thus far, no effect on glucocorticoid output has been described, as LDL-cholesterol levels usually remain within the physiological range. However, novel statin-based treatment regimens that dramatically decrease LDL-cholesterol levels are currently employed. Here, we assessed whether inhibition of cholesterol synthesis under these relatively hypocholesterolemic conditions may alter adrenal glucocorticoid output. MethodsHypocholesterolemic apolipoprotein A1 (apoA1) knockout mice were administered high dose simvastatin twice daily for 3 days. ResultsSimvastatin treatment did not change plasma cholesterol levels or modify the adrenal expression levels of genes involved in cholesterol metabolism. However, simvastatin treatment lowered basal plasma levels of the primary glucocorticoid corticosterone (−62%; p < 0.05). Upon injection with adrenocorticotropic hormone, control-treated apoA1 knockout mice already showed only a mild increase in plasma corticosterone levels, indicative of relative glucocorticoid insufficiency. Importantly, simvastatin treatment further diminished the adrenal glucocorticoid response to adrenocorticotropic hormone exposure (two-way ANOVA p < 0.05 for treatment). Peak corticosterone levels were 49% lower (p < 0.01) upon simvastatin treatment. ConclusionsWe have shown that simvastatin treatment aggravates the glucocorticoid insufficiency associated with hypocholesterolemia in mice. Our data suggest that (1) HMG-CoA reductase activity controls the adrenal steroidogenic capacity under hypocholesterolemic conditions and (2) imply that it might be important to monitor adrenal function in humans subjected to statin-based treatments aimed at achieving sub-physiological LDL-cholesterol levels, as these may potentially execute a negative impact on the glucocorticoid function in humans.
Highlights
Glucocorticoids, through an interaction with their cognate nuclear glucocorticoid receptor, modulate a great variety of physiological processes, including glucose metabolism and inflammation
Previous studies using gene knockout mice have indicated that, probably since high-density lipoprotein (HDL) is the predominant lipoprotein species circulating in murine plasma, HDL represents the major source of cholesterol utilized for glucocorticoid synthesis in mice [3,5,6]
To identify a potential effect on steroidogenesis of statinmediated disruption of adrenal de novo cholesterol synthesis under hypocholesterolemic conditions, we determined the impact of simvastatin treatment on the glucocorticoid function of apolipoprotein A1 (apoA1) deficient mice
Summary
Glucocorticoids, through an interaction with their cognate nuclear glucocorticoid receptor, modulate a great variety of physiological processes, including glucose metabolism and inflammation. Statin treatment disrupts HMG-CoA reductase-mediated endogenous cholesterol synthesis and lowers plasma LDL-cholesterol levels. Statin treatment can theoretically impair adrenal steroid hormone synthesis, far, no effect on glucocorticoid output has been described, as LDL-cholesterol levels usually remain within the physiological range. Simvastatin treatment lowered basal plasma levels of the primary glucocorticoid corticosterone (À62%; p < 0.05). Upon injection with adrenocorticotropic hormone, control-treated apoA1 knockout mice already showed only a mild increase in plasma corticosterone levels, indicative of relative glucocorticoid insufficiency. Our data suggest that (1) HMG-CoA reductase activity controls the adrenal steroidogenic capacity under hypocholesterolemic conditions and (2) imply that it might be important to monitor adrenal function in humans subjected to statin-based treatments aimed at achieving sub-physiological LDL-cholesterol levels, as these may potentially execute a negative impact on the glucocorticoid function in humans
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