simvastatin treatment aggravates the glucocorticoid insufficiency associated with hypocholesterolemia in mice

Accepted Manuscript Simvastatin treatment aggravates the glucocorticoid insufficiency associated with hypocholesterolemia in mice Amber B Ouweneel, Ronald J van der Sluis, Joya E Nahon, Miranda Van Eck, Menno Hoekstra PII: S0021-9150(17)30066-7 DOI: 10.1016/j.atherosclerosis.2017.02.014 Reference: ATH 14963 To appear in: Atherosclerosis Received Date: 13 October 2016 Revised Date: 30 January 2017 Accepted Date: 17 February 2017 Please cite this article as: Ouweneel AB, van der Sluis RJ, Nahon JE, Van Eck M, Hoekstra M, Simvastatin treatment aggravates the glucocorticoid insufficiency associated with hypocholesterolemia in mice, Atherosclerosis (2017), doi: 10.1016/j.atherosclerosis.2017.02.014 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT Simvastatin treatment aggravates the glucocorticoid insufficiency associated with hypocholesterolemia in mice Amber B Ouweneel, Ronald J van der Sluis, Joya E Nahon, Miranda Van Eck, Menno RI PT Hoekstra# Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug # M AN U SC Research, Gorlaeus Laboratories, Leiden, The Netherlands Corresponding author Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, The Netherlands TE D E-mail address: Hoekstra@lacdr.leidenuniv.nl (M Hoekstra) AC C EP Keywords: cholesterol synthesis, simvastatin, adrenal, glucocorticoid, steroidogenesis, mice ACCEPTED MANUSCRIPT ABSTRACT Background and aims: Statin treatment disrupts HMG-CoA reductase-mediated endogenous RI PT 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 SC physiological range However, novel statin-based treatment regimens that dramatically decrease LDL-cholesterol levels are currently employed Here, we assessed whether alter adrenal glucocorticoid output M AN U inhibition of cholesterol synthesis under these relatively hypocholesterolemic conditions may Methods: Hypocholesterolemic apolipoprotein A1 (apoA1) knockout mice were administered high dose simvastatin twice daily for days Results: Simvastatin treatment did not change plasma cholesterol levels or modify the TE D adrenal expression levels of genes involved in cholesterol metabolism However, simvastatin treatment lowered basal plasma levels of the primary glucocorticoid corticosterone (-62%; p