A revised Oxysterol Hypothesis highlighting the special roles played by 24(S),25-Epoxycholesterol

First proposed in 1978, the Oxysterol Hypothesis asserted that oxysterols exert feedback regulation on cholesterol synthesis rather than cholesterol itself. We argue for a revised Oxysterol Hypothesis focussing on recent findings regarding one oxysterol in particular. 24(S),25-epoxycholesterol (24,25EC) is synthesised by a shunt in the cholesterol synthesis pathway, in addition to being produced in the brain from a cholesterol precursor by a sterol hydroxylase (CYP46A1). 24,25EC is implicated in biological processes far beyond just cholesterol metabolism, including being an agonist for Smoothened which transduces the signal in the Hedgehog development pathway, and exerting profound effects on immune functions. We discuss how manipulating 24,25EC is of clinical interest in treating a wide range of disorders, including liver diseases, neurological diseases, and cancers.