Cholesterol 24-Hydroxylase: an enzyme of cholesterol turnover in the brain
Open accessAbstract
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.
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When neurons require cholesterol turnover or accumulate too much cholesterol or its intermediates, Cyp46a1 hydroxylates cholesterol to produce 24S-hydroxycholesterol, allowing egress by one-way diffusion into the circulation across the blood brain barrier.
“When neurons require cholesterol turnover or accumulate too much cholesterol or its intermediates, the cytochrome P450 oxidase Cyp46a1 hydroxylates cholesterol to produce 24S-hydroxycholesterol (24SOHC), allowing for egress by one-way diffusion into the circulation across the BBB (Fig. 4a)31.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [31]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredCholesterol turnover is required to produce geranylgeraniol, a product of HMGCR upstream of SQLE that is essential for learning and synaptic plasticity.
“Cholesterol turnover is also required to produce geranylgeraniol, a product of HMGCR upstream of SQLE that is essential for learning and synaptic plasticity31, and is important for the interaction between neurons and astrocytes at the synapse28.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [31]
The Summary and Outlook and ‘Rescue by Geranylgeraniol’ sections link reduced brain cholesterol turnover to reduced biosynthetic flow, learning deficits in mice, and impaired hippocampal LTP that geranylgeraniol restores. The copy does not establish the claim’s specific HMGCR-to-SQLE placement, and it says the active form may be geranylgeraniol, geranylgeranyl diphosphate, or another metabolite. The neuron–astrocyte clause has a separate citation and is not assessed here; the indexed passages provide no page numbers. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe catabolic pathway facilitated by cholesterol 24-hydroxylase (CYP46A1) is the major route for eliminating cholesterol from the CNS and is a key player in the maintenance of cholesterol homeostasis in the brain.
“This catabolic pathway, which is facilitated by cholesterol 24-hydroxylase (CYP46A1), is the major route for eliminating cholesterol from the CNS, and is therefore a key player in the maintenance of cholesterol homeostasis in the brain (Lütjohann et al., 1996; Russell et al., 2009).”
From Suppression of brain cholesterol synthesis in male Mecp2-deficient mice is age dependent and not accompanied by a concurrent change in the rate of fatty acid synthesis (2017) · cites this paper as Russell et al., 2009
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- Authors
- Russell, D. W., Halford, R. W., Ramirez, D. M. O., Shah, R., & Kotti, T.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Venue
- Annual Review of Biochemistry
- Publisher
- Annual Reviews
- Published
- 2009-06-01
- Volume
- 78
- Issue
- 1
- Pages
- 1017-1040
- ISSN
- 0066-4154 (ISSN-L)
- 1545-4509
- PMC
- PMC2837268
- OpenAlex
- W2128990583
- Cited by
- 317
- References
- 113
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 27 · 2023: 16 · 2022: 23 · 2021: 40 · 2020: 26 · 2019: 20 · 2018: 16 · 2017: 12 · 2016: 18 · 2015: 14 · 2014: 13 · 2013: 13 · 2012: 16
- FWCI
- 2.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annual Review of Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Welch Foundation
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-20948, P01HL020948)
- National Institute of General Medical Sciences (GM 69338, U54GM069338)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 81182, PL1DK081182)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
- Keywords
- cholesterol 24-hydroxylase, cholesterol turnover, brain cholesterol metabolism, cytochrome P450, cholesterol biosynthesis, learning and memory, synaptic plasticity, hippocampal neurons, cortical neurons
- MeSH terms
- Cholesterol 24-Hydroxylase, Animals, Brain, Cholesterol, Hippocampus, Humans, Learning, Neurons, Steroid Hydroxylases, Gene Expression Regulation, Enzymologic
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