title: Simvastatin treatment aggravates the glucocorticoid insufficiency associated with hypocholesterolemia in mice.
abstract: Statin 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.
  
  
  
  Hypocholesterolemic apolipoprotein A1 (apoA1) knockout mice were administered high dose simvastatin twice daily for 3 days.
  
  
  
  Simvastatin 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.
  
  
  
  We 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.
authors.affiliation: Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands.
authors.forename: Amber B
authors.initials: AB
authors.lastname: Ouweneel
authors.affiliation: Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: van der Sluis
authors.affiliation: Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands.
authors.forename: Joya E
authors.initials: JE
authors.lastname: Nahon
authors.affiliation: Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
authors.affiliation: Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands. Electronic address: Hoekstra@lacdr.leidenuniv.nl.
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
mesh_terms: D000304:Adrenal Cortex Function Tests; D000311:Adrenal Glands / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D000309:Adrenal Insufficiency / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage; D000818:Animals; D016632:Apolipoprotein A-I / Q000172:deficiency / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D002784:Cholesterol / Q000097:blood*; D003345:Corticosterone / Q000097:blood / Q000172:deficiency*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D019821:Simvastatin / Q000633:toxicity*
chemical_list: D016632:Apolipoprotein A-I; D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D000324:Adrenocorticotropic Hormone; D002784:Cholesterol; D019821:Simvastatin; D003345:Corticosterone
keywords: Adrenal; Cholesterol synthesis; Glucocorticoid; Mice; Simvastatin; Steroidogenesis