Cholesterol-Dependent Degradation of Squalene Monooxygenase, a Control Point in Cholesterol Synthesis beyond HMG-CoA Reductase
Open accessAbstract
Exquisite control of cholesterol synthesis is crucial for maintaining homeostasis of this vital yet potentially toxic lipid. Squalene monooxygenase (SM) catalyzes the first oxygenation step in cholesterol synthesis, acting on squalene before cyclization into the basic steroid structure. Using model cell systems, we found that cholesterol caused the accumulation of the substrate squalene, suggesting that SM may serve as a flux-controlling enzyme beyond 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR, considered as rate limiting). Cholesterol accelerated the proteasomal degradation of SM which required the N-terminal domain, partially conserved in vertebrates but not in lower organisms. Unlike HMGR, SM degradation is not mediated by Insig, 24,25-dihydrolanosterol, or side-chain oxysterols, but rather by cholesterol itself. Importantly, SM's N-terminal domain conferred cholesterol-regulated turnover on heterologous fusion proteins. Furthermore, proteasomal inhibition almost totally eliminated squalene accumulation, highlighting the importance of this degradation mechanism for the control of SM and suggesting this as a possible control point in cholesterol synthesis.
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Cholesterol homeostasis is maintained by negative feedback regulation of genes and their encoded enzymes in the pathway, including the rate-limiting enzymes HMGCR and SQLE.
“Cholesterol homeostasis is maintained by negative feedback regulation of genes and their encoded enzymes in the pathway, including the rate limiting enzymes HMG CoA reductase (HMGCR) and SQLE20–22.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [20]
The Introduction identifies HMGCR as a major rate-limiting control point, and the passage on cholesterol treatment reports reduced mRNA levels for both HMGCR and SQLE (Abstract, Figure 1E). The paper also reports cholesterol-dependent degradation of SQLE's enzyme, but describes SQLE as a *possible* control point that may become rate-limiting under acute cholesterol treatment—not an established rate-limiting enzyme generally. (LLM, conf=0.86)
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Cites
Studies on Squalene Epoxidase of Rat Liver
Yamamoto, S., & Bloch, K. (1970) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)77144-0 · Cited by 163 · see citing works
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Research works printed but not linked: 3
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Mechanisms and regulation of cholesterol homeostasis
Luo, J., Yang, H., & Song, B.-L. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0190-7 · Cited by 1,980 · see citing works
A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome
Buchovecky, C. M., Turley, S. D., Brown, H. M., Kyle, S. M., McDonald, J. G., Liu, B., Pieper, A. A., Huang, W., Katz, D. M., Russell, D. W., et al. (2013) · Nature Genetics · doi:10.1038/ng.2714 · Cited by 234 · see citing works
Disorders in the initial steps of steroid hormone synthesis
Miller, W. L. (2017) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.03.009 · Cited by 205 · see citing works
Foresti, O., Ruggiano, A., Hannibal-Bach, H. K., Ejsing, C. S., & Carvalho, P. (2013) · eLife · doi:10.7554/elife.00953 · Cited by 205 · see citing works
MeCP2 co-ordinates liver lipid metabolism with the NCoR1/HDAC3 corepressor complex
Kyle, S. M., Saha, P. K., Brown, H. M., Chan, L. C., & Justice, M. J. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw156 · Cited by 84 · see citing works
What dictates the accumulation of desmosterol in the developing brain?
Jansen, M., Wang, W., Greco, D., Bellenchi, G. C., di Porzio, U., Brown, A. J., & Ikonen, E. (2013) · The FASEB Journal · doi:10.1096/fj.12-211235 · Cited by 42 · see citing works
Self-citation
- Authors
- Gill, S., Stevenson, J., Kristiana, I., & Brown, A. J.
- Affiliations
- UNSW Sydney (AU)
- Corresponding author
- Brown, Andrew J.
- ORCID
- Brown, Andrew J.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-03
- Volume
- 13
- Issue
- 3
- Pages
- 260-273
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2024141615
- Cited by
- 304
- References
- 1
- Citations by year
- 2026: 15 · 2025: 22 · 2024: 25 · 2023: 28 · 2022: 31 · 2021: 21 · 2020: 31 · 2019: 26 · 2018: 19 · 2017: 15 · 2016: 12 · 2015: 13 · 2014: 12 · 2013: 11 · 2012: 11
- FWCI
- 14.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- 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 › Steroid Chemistry and Biochemistry
- Keywords
- squalene monooxygenase, cholesterol biosynthesis, proteasomal degradation, N-terminal domain, squalene accumulation, flux control, HMG-CoA reductase, SREBP, oxysterols, sterol homeostasis
- MeSH terms
- Amino Acid Sequence, Animals, Cell Line, Cholesterol, Cricetulus, Cricetinae, Humans, Hydroxymethylglutaryl CoA Reductases, Molecular Sequence Data, Protein Processing, Post-Translational, Squalene, Sequence Alignment, CHO Cells, Protein Structure, Tertiary, Ubiquitin, Proteasome Endopeptidase Complex, Squalene Monooxygenase
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