Oxysterols

Oxysterols are oxygenated derivatives of cholesterol, formed when one or more oxygen-containing groups are added to the sterol backbone. They occur in animal tissues and plasma as products of normal lipid metabolism, and they can arise both enzymatically and non-enzymatically through oxidative processes.

Enzymatic formation involves several cytochrome P450 enzymes. In the brain, cholesterol 24-hydroxylase (CYP46A1) produces 24S-hydroxycholesterol, which helps eliminate excess brain cholesterol. Other tissues generate 25-hydroxycholesterol (via CH25H) and 27-hydroxycholesterol (via CYP27A1). Some oxysterols also act as intermediates in the synthesis of bile acids. Through these pathways, oxysterols participate in the regulation of cholesterol synthesis, uptake, and efflux.

Non-enzymatic oxidation, often driven by reactive oxygen species, yields oxysterols such as 7-hydroxycholesterol and 7-ketocholesterol. These oxidation products can accumulate in oxidized low-density lipoprotein and various tissues, where they may contribute to cytotoxicity, inflammation, and the development of atherosclerosis and neurodegenerative conditions.

Physiological and pathological roles are largely mediated by interactions with cellular receptors and transcriptional pathways. Many oxysterols are ligands for liver X receptors (LXRs), which regulate genes involved in cholesterol homeostasis, lipid metabolism, and inflammatory responses. Some oxysterols can influence signaling through other receptors in tissue-specific ways, including estrogen-related pathways.

Because oxysterol levels reflect cholesterol turnover and oxidative status, they are studied as potential biomarkers for metabolic and neurodegenerative disorders and are a focus of research into therapeutic targets for lipid-related diseases.