Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)
Open accessAbstract
3-Hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the target of the statins, important drugs that lower blood cholesterol levels and treat cardiovascular disease. Consequently, the regulation of HMGCR has been investigated in detail. However, this enzyme acts very early in the cholesterol synthesis pathway, with ∼20 subsequent enzymes needed to produce cholesterol. How they are regulated is largely unexplored territory, but there is growing evidence that enzymes beyond HMGCR serve as flux-controlling points. Here, we introduce some of the known regulatory mechanisms affecting enzymes beyond HMGCR and highlight the need to further investigate their control.
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The values for brain cholesterol concentration in 7-day-old animals, and to some extent in 14-day-old mice, include desmosterol, an immediate precursor of cholesterol.
“Another point regarding the brain cholesterol concentration measurements is that the values for the 7-day-old animals in particular, and to some extent for the 14-day-old mice, include desmosterol, an immediate precursor of cholesterol (Paoletti et al., 1965; Sharpe and Brown, 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 Sharpe and Brown, 2013
The paper’s discussion of DHCR24 identifies desmosterol as its substrate in the cholesterol-synthesis pathway and cites work on desmosterol accumulation in the developing brain (indexed as Abstract; page unavailable). It does not say that cholesterol concentration measurements in 7-day-old or 14-day-old mice included desmosterol, so the measurement-specific claim is unsupported by this source. (LLM, conf=0.80)
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Djelti, F., Braudeau, J., Hudry, E., Dhenain, M., Varin, J., Bièche, I., Marquer, C., Chali, F., Ayciriex, S., Auzeil, N., et al. (2015) · Brain · doi:10.1093/brain/awv166 · Cited by 223 · see citing works
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Lütjohann, D., Lopez, A. M., Chuang, J., Kerksiek, A., & Turley, S. D. (2018) · Lipids · doi:10.1002/lipd.12041 · Cited by 11 · see citing works
- Authors
- Sharpe, L. J., & Brown, A. J.
- Affiliations
- The University of Sydney (AU)
- UNSW Sydney (AU)
- Corresponding author
- Brown, Andrew J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-06
- Volume
- 288
- Issue
- 26
- Pages
- 18707-18715
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3696645
- OpenAlex
- W2007387279
- Cited by
- 382
- References
- 5
- Citations by year
- 2026: 23 · 2025: 31 · 2024: 34 · 2023: 36 · 2022: 31 · 2021: 39 · 2020: 34 · 2019: 36 · 2018: 28 · 2017: 22 · 2016: 21 · 2015: 25 · 2014: 15 · 2013: 6
- FWCI
- 3.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
- Keywords
- cholesterol biosynthesis, HMGCR, statins, enzyme regulation, flux control, cholesterol synthesis pathway, cardiovascular disease
- MeSH terms
- Animals, Cholesterol, Endoplasmic Reticulum, Humans, Hydroxymethylglutaryl CoA Reductases, Protein Processing, Post-Translational, Alternative Splicing, Protein Isoforms, Squalene Monooxygenase, Sterol Regulatory Element Binding Proteins
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