Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover
Open accessAbstract
Most cholesterol turnover takes place in the liver and involves the conversion of cholesterol into soluble and readily excreted bile acids. The synthesis of bile acids is limited to the liver, but several enzymes in the bile acid biosynthetic pathway are expressed in extra-hepatic tissues and there also may contribute to cholesterol turnover. An example of the latter type of enzyme is cholesterol 24-hydroxylase, a cytochrome P450 (CYP46A1) that is expressed at 100-fold higher levels in the brain than in the liver. Cholesterol 24-hydroxylase catalyzes the synthesis of the oxysterol 24(S)-hydroxycholesterol. To assess the relative contribution of the 24-hydroxylation pathway to cholesterol turnover, we performed balance studies in mice lacking the cholesterol 24-hydroxylase gene (Cyp46a1-/- mice). Parameters of hepatic cholesterol and bile acid metabolism in the mutant mice remained unchanged relative to wild type controls. In contrast to the liver, the synthesis of new cholesterol was reduced by approximately 40% in the brain, despite steady-state levels of cholesterol being similar in the knockout mice. These data suggest that the synthesis of new cholesterol and the secretion of 24(S)-hydroxycholesterol are closely coupled and that at least 40% of cholesterol turnover in the brain is dependent on the action of cholesterol 24-hydroxylase. We conclude that cholesterol 24-hydroxylase constitutes a major tissue-specific pathway for cholesterol turnover in the brain.
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To maintain homeostasis, cholesterol can be converted into the oxysterol 24(S)-hydroxycholesterol (24S-OHC) by the neuron-specific enzyme CYP46A1.
“To maintain homeostasis, cholesterol can be converted into the oxysterol 24(S)-hydroxycholesterol (24S-OHC) by the neuron-specific enzyme CYP46A1 (figure 4a) [162].”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [162]
The Abstract states that CYP46A1 converts cholesterol to 24(S)-hydroxycholesterol, and the Discussion links this pathway to maintaining brain cholesterol homeostasis. The paper reports expression in neurons of the adult brain, but also reports low-level expression in the liver and testis, so it does not establish that the enzyme is strictly neuron-specific. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe only other mouse mutant to show decreased brain cholesterol synthesis is Cyp46a1, which lacks 24SOHC, required for brain cholesterol turnover.
“The only other mouse mutant to show decreased brain cholesterol synthesis is Cyp46a1, which lacks 24SOHC, required for brain cholesterol turnover44.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [44]
The Results report that Cyp46a1 knockout mice had about 40% lower brain cholesterol synthesis, and the Discussion identifies cholesterol 24-hydroxylase as responsible for at least 40% of brain cholesterol turnover (pages unavailable). The paper does not establish that this is the only other mouse mutant with reduced brain cholesterol synthesis. It also reports low but measurable brain 24(S)-hydroxycholesterol in the knockout mice, rather than its complete absence. (LLM, conf=0.86)
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- Authors
- Lund, E. G., Xie, C., Kotti, T., Turley, S. D., Dietschy, J. M., & Russell, D. W.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Russell, David W.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 278
- Issue
- 25
- Pages
- 22980-22988
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2002793897
- Cited by
- 421
- References
- 55
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 14 · 2023: 27 · 2022: 28 · 2021: 29 · 2020: 21 · 2019: 20 · 2018: 18 · 2017: 11 · 2016: 18 · 2015: 17 · 2014: 17 · 2013: 21 · 2012: 15
- FWCI
- 15.38
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R37-HL 09610, R37HL009610, P01 HL-20948, P01HL020948)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- cholesterol 24-hydroxylase, CYP46A1, 24S-hydroxycholesterol, oxysterols, bile acid synthesis, hepatic cholesterol metabolism, knockout mice
- MeSH terms
- Cholesterol 24-Hydroxylase, Alleles, Animals, beta-Galactosidase, Brain, Cholesterol, Cholesterol, Dietary, Embryonic and Fetal Development, Kinetics, Liver, RNA, Messenger, Steroid Hydroxylases, Transcription, Genetic, Restriction Mapping, Gene Expression Regulation, Enzymologic, Mice, Knockout, Gene Expression Regulation, Developmental, Mice
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