CYP46A1

CYP46A1 is a member of the cytochrome P450 superfamily and a neuronal microsomal enzyme that hydroxylates cholesterol to 24S-hydroxycholesterol in the brain, enabling cholesterol removal from the central nervous system. This brain-specific pathway complements de novo cholesterol synthesis, providing a mechanism for cholesterol turnover in the CNS.

The enzyme is primarily expressed in neurons and localizes to the endoplasmic reticulum. It uses NADPH via the P450 reductase to perform monooxygenation of cholesterol, producing 24S-hydroxycholesterol. The product is more polar than cholesterol and can cross the blood–brain barrier, allowing cholesterol-derived material to be eliminated from the brain.

CYP46A1 plays a central role in brain cholesterol homeostasis. In the CNS, cholesterol cannot efficiently exit the brain without conversion, so CYP46A1-mediated turnover is a key pathway for maintaining lipid balance. Brain cholesterol is largely synthesized in situ, and turnover is relatively slow; changes in CYP46A1 activity can influence the rate at which cholesterol is removed. 24S-hydroxycholesterol also functions as a signaling molecule, acting as an endogenous ligand for liver X receptors and influencing cholesterol efflux pathways.

Gene and regulation: The CYP46A1 gene encodes the brain-specific enzyme. Expression is predominantly neuronal, with activity observed in regions such as the cortex, hippocampus, and cerebellum. Regulation appears responsive to neuronal activity and cholesterol status, with transcriptional inputs potentially involving oxysterol signaling and nuclear receptors such as LXR and SREBP, reflecting the integration of cholesterol balance with neuronal function.

Clinical and research notes: Altered brain cholesterol turnover has been associated with neurodegenerative conditions, and CYP46A1 is a focal point in research exploring therapies to modulate brain cholesterol homeostasis. Pharmacological modulation of CYP46A1 activity is under investigation as a potential avenue for cognitive or neuroprotective strategies.