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 7α-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 7α-hydroxycholesterol into 7α-hydroxy-4-cholesten-3-one was investigated and I concluded that only one
enzyme is required and that no
isomerase is involved. Accumulation of 7α-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 7α-hydroxy-4-cholesten-3-one. We also showed that 7α-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 disturbances 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.