Quantitation of two pathways for cholesterol excretion from the brain in normal mice and mice with neurodegeneration
Open accessAbstract
Although the pool of cholesterol in the adult central nervous system (CNS) is large and of constant size, little is known of the process(es) involved in regulation of sterol turnover in this pool. In 7-week-old mice, net excretion of cholesterol from the brain equaled 1.4 mg/day/kg body weight, and from the whole animal was 179 mg/day/kg. Deletion of cholesterol 24-hydroxylase, an enzyme highly expressed in the CNS, did not alter brain growth or myelination, but reduced sterol excretion from the CNS 64% to 0.5 mg/day/kg. In mice with a mutation in the Niemann-Pick C gene that had ongoing neurodegeneration, sterol excretion from the CNS was increased to 2.3 mg/day/kg. Deletion of cholesterol 24-hydroxylase activity in these animals reduced net excretion only 22% to 1.8 mg/day/kg. Thus, at least two different pathways promote net sterol excretion from the CNS. One uses cholesterol 24-hydroxylase and may reflect sterol turnover in large neurons in the brain. The other probably involves the movement of cholesterol or one of its metabolites across the blood-brain barrier and may more closely mirror sterol turnover in pools such as glial cell membranes and myelin.
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There is compelling evidence that the rate of cholesterol synthesis in the CNS shifts in accordance with loss- or gain-of-function changes in Cyp46a1 expression.
“There is compelling evidence that the rate of cholesterol synthesis in the CNS shifts in accordance with loss- or gain-of-function changes in Cyp46a1 expression.”
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 Xie et al., 2003
The section on net cholesterol movement reports that CNS cholesterol synthesis was 40% lower in Cyp46a1 knockout mice than in controls, supporting the loss-of-function part of the claim. The paper does not establish a corresponding synthesis change from gain-of-function Cyp46a1 expression; its neurodegeneration section reports essentially unchanged CYP46A1 mRNA and protein levels. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe technique employed for measuring in vivo cholesterol synthesis in whole brain or specific CNS regions has been utilized in several laboratories in an array of genetically altered mouse models.
“The technique employed for these measurements has been utilized in several laboratories for measuring, in vivo, the rate of cholesterol synthesis in either the whole brain, or specific regions of the CNS, in an array of genetically altered mouse models (Xie et al., 2003; Halford and Russell, 2009; Bryleva et al., 2010; Liu et al., 2010; Aqul et al., 2011; Suzuki et al., 2013).”
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 Xie et al., 2003
In the Cyp46a1 knockout mouse, the marked reduction in production of 24S-OHC and its elimination from the brain is offset by a substantial fall in cholesterol synthesis in all major regions.
“In the Cyp46a1 knockout mouse, the marked reduction in the production of 24S-OHC and its elimination from the brain is offset by a substantial fall in cholesterol synthesis in all the major regions (Xie et al., 2003).”
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 Xie et al., 2003
De novo cholesterol synthesis assayed by in vivo incorporation of 3H2O into sterols confirmed that sterol synthesis decreased in the adult brain of B6.Mecp2tm1.1Jae/Y.
“Similarly, de novo cholesterol synthesis assayed by the in vivo incorporation of 3H2O into sterols34 confirmed that sterol synthesis decreased in the adult brain of B6.Mecp2tm1.1Jae/Y”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [34]
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Self-citation
- Authors
- Xie, C., Lund, E. G., Turley, S. D., Russell, D. W., & Dietschy, J. M.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Dietschy, John M.
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2003-09
- Volume
- 44
- Issue
- 9
- Pages
- 1780-1789
- ISSN
- 0022-2275 (ISSN-L)
- OpenAlex
- W2155518349
- Cited by
- 159
- References
- 4
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 1 · 2023: 4 · 2022: 8 · 2021: 7 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 6 · 2014: 5 · 2013: 7 · 2012: 11
- FWCI
- 7.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- W. M. Keck Foundation
- Welch Foundation (I-0971)
- National Institutes of Health (HL20948)
- National Heart, Lung, and Blood Institute (R37-HL 09610, R37HL009610, P50 HL20948)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- cholesterol excretion, brain cholesterol, cholesterol 24-hydroxylase, Niemann-Pick disease type C, neurodegeneration, blood-brain barrier, myelin, glial cells, mice
- MeSH terms
- Cholesterol 24-Hydroxylase, Aging, Animals, Brain, Cholesterol, Cholesterol 7-alpha-Hydroxylase, Female, Male, Nerve Degeneration, RNA, Messenger, Sex Characteristics, Steroid Hydroxylases, Gene Deletion, Mice, Knockout, Mice, Cholestanetriol 26-Monooxygenase
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