Five decades with oxysterols

I have been involved in research on oxysterols since 1963 and this review is intended to cover some of the most important aspects of this work. The first project dealed with 7 alpha-hydroxy-4-cholesten-3-one. My successful synthesis of this steroid with high specific radioactivity allowed a demonstration that it is a bile acid precursor. The mechanism of conversion of 7 alpha-hydroxycholesterol into 7 alpha-hydroxy-4-cholesten-3-one was investigated and I concluded that only one enzyme is required and that no isomerase is involved. Accumulation of 7 alpha-hydroxy-4-cholesten-3-one in patients with lack of sterol 27-hydroxylase (Cerebrotendinous xanthomatosis was shown to be an important pathogenetic factor. This disease is characterized by cholestanol-containing xanthomas in tendons and brain and we could show that most of this cholestanol is formed from 7 alpha-hydroxy-4-cholesten-3-one. We also showed that 7 alpha-hydroxy-4-cholesten-3-one passes the blood-brain barrier. In contrast to cholesterol itself, side-chain oxidized oxysterols have a high capacity to pass lipophilic membranes. We demonstrated conversion of cholesterol into 27-hydroxycholesterol to be a significant mechanism for elimination of cholesterol from macrophages. We also showed that conversion of cholesterol into 24S-hydroxycholesterol is important for elimination of cholesterol from the brain. Side-chain oxidized oxysterols have a high capacity to affect critical genes in cholesterol turnover in vitro. Most of the published in vitro experiments with oxysteroids are highly unphysiological, however. Mouse models studied in my laboratory with high or low levels of 27-hydroxycholesterol have little or no disturbancies in cholesterol homeostasis. 24S-hydroxycholesterol is an efficient ligand to LXR and suggested to be important for cholesterol homeostasis in the brain. We recently developed a mouse model with markedly increased levels of this oxysterol in circulation and brain. This overexpression had however only a very modest effect on cholesterol turnover. We concluded that oxysterols are not the master regulators of cholesterol homeostasis in vivo suggested previously. (C) 2012 Elsevier Masson SAS. All rights reserved.