Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake
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This paper describes a convergent mechanism for the feedback control of cholesterol synthesis and uptake mediated by SREBPs, membrane bound transcription factors. Endoplasmic reticulum (ER) bound SREBPs form complexes with Scap, a polytopic ER protein. In sterol-overloaded cells, Scap/SREBP binds to Insig-1, which retains the complex in the ER. Upon sterol deprivation, the Scap/SREBP complex dissociates from Insig-1, which is then ubiquitinated on lysines 156 and 158 and degraded in proteasomes. Scap/SREBP moves to the Golgi, where SREBP is processed to liberate a nuclear fragment that activates genes for cholesterol synthesis and uptake and the gene for Insig-1. Ubiquitination is not necessary for release of Scap/SREBP from Insig-1, but it establishes a requirement for synthesis of new Insig-1 for feedback inhibition. When the new Insig-1 and cholesterol converge on Scap, Scap/SREBP binds to Insig-1, preventing ubiquitination. The Insig-1/Scap/SREBP complex accumulates in the ER, ready for liberation when the cell is again sterol deprived.
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When 25HC binds to Insig1, it stabilizes the protein by reducing proteasomal degradation of Insig1, thus promoting its interaction with Scap-Srebp2.
“When 25HC binds to Insig1, it also stabilizes the protein by reducing proteasomal degradation of Insig1 thus promoting its interaction with Scap-Srebp2 (60).”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [60]
Insig1 is a target of the Srebp-signaling pathway, and its expression is reduced in the presence of 25HC.
“Since Insig1 is a target of the Srebp- signaling pathway (60), expression of Insig1 is also reduced in the presence of 25HC.”
From Regulation of astrocyte lipid metabolism and ApoE secretion by the microglial oxysterol, 25-hydroxycholesterol (2023) · cites this paper as [60]
Cites
Regulation of the mevalonate pathway
Goldstein, J. L., & Brown, M. S. (1990) · Nature · doi:10.1038/343425a0 · Cited by 5,394 · see citing works
Self-citationSREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Horton, J. D., Goldstein, J. L., & Brown, M. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0215593 · Cited by 4,092 · see citing works
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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
Regulation of Sterol Synthesis in Eukaryotes
Espenshade, P. J., & Hughes, A. L. (2007) · Annual Review of Genetics · doi:10.1146/annurev.genet.41.110306.130315 · Cited by 593 · see citing works
DeBose-Boyd, R. A. (2008) · Cell Research · doi:10.1038/cr.2008.61 · Cited by 391 · see citing works
Using genetic markers to orient the edges in quantitative trait networks: The NEO software
Aten, J. E., Fuller, T. F., Lusis, A. J., & Horvath, S. (2008) · BMC Systems Biology · doi:10.1186/1752-0509-2-34 · Cited by 147 · see citing works
Cashikar, A. G., Toral-Rios, D., Timm, D., Romero, J., Strickland, M., Long, J. M., Han, X., Holtzman, D. M., & Paul, S. M. (2023) · Journal of Lipid Research · doi:10.1016/j.jlr.2023.100350 · Cited by 72 · see citing works
Cholesterol: From Feeding to Gene Regulation
Martini, C., & Pallottini, V. (2007) · Genes & Nutrition · doi:10.1007/s12263-007-0049-y · Cited by 53 · see citing works
Metabolic injury of hepatocytes promotes progression of NAFLD and AALD
Carvalho-Gontijo, R., Han, C., Zhang, L., Zhang, V., Hosseini, M., Mekeel, K., Schnabl, B., Loomba, R., Karin, M., Brenner, D. A., et al. (2022) · Seminars in Liver Disease · doi:10.1055/s-0042-1755316 · Cited by 23 · see citing works
- Authors
- Gong, Y., Lee, J. N., Lee, P. C. W., Goldstein, J. L., Brown, M. S., & Ye, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Goldstein, Joseph L.
- Brown, Michael S.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2006-01
- Volume
- 3
- Issue
- 1
- Pages
- 15-24
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2130820087
- Cited by
- 262
- References
- 2
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 13 · 2023: 17 · 2022: 12 · 2021: 7 · 2020: 20 · 2019: 13 · 2018: 13 · 2017: 13 · 2016: 15 · 2015: 12 · 2014: 18 · 2013: 14 · 2012: 9
- FWCI
- 12.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-20948, P01HL020948)
- 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 › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- INSIG1, SREBP, SCAP, ubiquitination, protein degradation, cholesterol biosynthesis, cholesterol absorption, feedback regulation, endoplasmic reticulum, Golgi apparatus, proteasome, transcriptional regulation
- MeSH terms
- Animals, Cholesterol, Cricetulus, Cricetinae, Humans, Hydroxycholesterols, Lysine, Membrane Proteins, Sterols, CHO Cells, Feedback, Physiological, Ubiquitin, Intracellular Signaling Peptides and Proteins, Sterol Regulatory Element Binding Proteins
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