Cholesterol 24-Hydroxylase: An Enzyme of Cholesterol Turnover in the Brain

Abstract

Cholesterol 24-hydroxylase is a highly conserved cytochrome P450 that is responsible for the majority of cholesterol turnover in the vertebrate central nervous system. The enzyme is expressed in neurons, including hippocampal and cortical neurons that are important for learning and memory formation. Disruption of the cholesterol 24-hydroxylase gene in the mouse reduces both cholesterol turnover and synthesis in the brain but does not alter steady-state levels of cholesterol in the tissue. The decline in synthesis reduces the flow of metabolites through the cholesterol biosynthetic pathway, of which one, geranylgeraniol diphosphate, is required for learning in the whole animal and for synaptic plasticity in vitro. This review focuses on how the link between cholesterol metabolism and higher-order brain function was experimentally established.

Tissue cholesterol content alterations in streptozotocin-induced diabetic rats

“…One is reverse cholesterol transport, which is mediated by ABC transporters, the class A scavenger receptor and ApoE. The other important pathway is the conversion of cholesterol into oxysterols [32] . In contrast to cholesterol, oxysterols are able to traverse the blood-brain barrier.…”

Epigenetic regulation of oxysterol formation

“…The organisation of the genome in eukaryotes is based on nucleosomes, nucleoprotein complexes that consist of 147 bp of DNA wound around an octameric complex made up of two copies of the histone 6 proteins H2A, H2B, H3 and H4 [9]. Histone protein H1 binds to a 20 bp linker region that connects nucleosomes together.…”

“…CYP46A1 encodes cholesterol 24-hydroxylase an enzyme which is highly expressed in the neurons of the central nervous system but which is virtually absent from other tissues [6]. CYP46A1 does not appear to be regulated in a similar manner to the other GROS and initial characterisation of the 11 CYP46A1 promoter revealed insensitivity to pathways known to regulate other GROS such as CYP7A1 and CYP27A1 [31].…”

“…GROS) are not universally present in different tissues and cells, with the consequence that particular organs are enriched with particular oxysterols, typically in relation the relative expression of the appropriate GROS [5]. For example, the brain contains relatively high amounts of 24S-hydroxycholesterol (24S-OHC) and its generative enzyme, cholesterol 24-hydroxylase (CYP46A1), is highly expressed in CNS neurons [6].…”

Neuronal cholesterol esterification by ACAT1 in Alzheimer's disease

“…Other transcription factors, including the nuclear receptors LXRs, control the expression of proteins involved in cholesterol transport (52,53), including apoE, ABCA1, ABCG1, and ABCG4 (54,55). In the brain, cholesterol can be enzymatically converted to 24SOH by Cyp46A1 (56); the concentration of 24SOH far exceeds those of other oxysterols in the brain (57)(58)(59). Cyp46A1 is a brain-specific enzyme; in mice lacking Cyp46A1, the 24SOH content in the brains is reduced by more than 95% (60), implying that almost all of the 24SOH present in the brain is produced through Cyp46A1.…”