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Switch-like Control of SREBP-2 Transport Triggered by Small Changes in ER Cholesterol: A Delicate Balance

Radhakrishnan, Arun, Goldstein, Joseph L., McDonald, Jeffrey G., Brown, Michael S.·2008·Cell Metabolism
DOI 10.1016/j.cmet.2008.10.008PMC PMC2652870
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Crossref · 10.1016/j.cmet.2008.10.008

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  • When activated by physiologic signals such as changes to cholesterol content in the ER membrane, SREBP-2 binds to LDLR mRNA.

    “When activated by physiologic signals such as changes to cholesterol content in the endoplasmic reticulum (ER) membrane (see section below on feedback inhibition), SREBP-2 binds to LDLR mRNA25.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [25]

    The Introduction (page unavailable) describes SREBP as a transcription factor whose active domain enters the nucleus and activates genes for cholesterol uptake; the Discussion says ER cholesterol controls that activation. The paper therefore describes regulation of gene transcription, not SREBP-2 binding to LDLR mRNA. (LLM, conf=0.84)

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  • When cholesterol levels are above 5 mol% of ER membrane lipid composition, SCAP interacts with cholesterol and INSIG to maintain inactive SREBP-2 in the ER membrane.

    “In contrast, when cholesterol levels are above 5mol% of ER membrane lipid composition, SCAP interacts with cholesterol and insulin-induced gene (INSIG), to maintain inactive SREBP-2 in the ER membrane (Fig. 4B)25.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [25]

  • A drop in ER cholesterol leads to a conformational change in SCAP, dissociation from INSIG, and COPII-mediated trafficking of the SCAP-SREBP complex to the Golgi.

    “A drop in cholesterol in the ER membrane leads to a conformational change in SCAP11,12, which leads to dissociation from INSIG and facilitates COPII-mediated trafficking of the SCAP-SREBP complex to the Golgi13–15.”

    From Haploid genetic screens identify SPRING/C12ORF49 as a determinant of SREBP signaling and cholesterol metabolism (2020) · cites this paper as [12]

  • SREBP2 is a transcriptional regulator of many genes involved in the cholesterol synthesis pathway in addition to LDLR.

    “In addition to LDLR, SREBP2 is also a transcriptional regulator of many other genes involved in the cholesterol synthesis pathway25,26.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [25]

  • A decrease in ER-membrane cholesterol content results in dissociation of INSIG from SCAP and COPII-dependent anterograde transport of the SCAP/SREBP complex to the Golgi.

    “A decrease in ER-membrane cholesterol content results in the dissociation of INSIG from SCAP, and COPII-dependent anterograde transport of the SCAP/SREBP complex to the Golgi4,5”

    From Hepatic SREBP signaling requires SPRING to govern systemic lipid metabolism in mice and humans (2023) · cites this paper as [4]

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Citations

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Research works printed but not linked: 37

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  2. Balch, 1985, Characterization of protein transport between successive compartments of the Golgi apparatus: asymmetric properties of donor and acceptor activities in a cell-free system, Arch. Biochem. Biophys., 240, 413, 10.1016/0003-9861(85)90046-3 · DOI
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  5. Brown, 1974, Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and inhibition of growth of human fibroblasts by 7-ketocholesterol, J. Biol. Chem., 249, 7306, 10.1016/S0021-9258(19)42106-6 · DOI · Paper page
  6. Brown, 1997, The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor, Cell, 89, 331, 10.1016/S0092-8674(00)80213-5 · DOI · Paper page
  7. Brown, 1975, Cholesteryl ester formation in cultured human fibroblasts: Stimulation by oxygenated sterols, J. Biol. Chem., 250, 4025, 10.1016/S0021-9258(19)41498-1 · DOI · Paper page
  8. Brown, 1978, Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductase, J. Biol. Chem., 253, 1121, 10.1016/S0021-9258(17)38120-6 · DOI
  9. Cao, 1996, Complementation of mutation in acyl-CoA: cholesterol acyltransferase (ACAT) fails to restore sterol regulation in ACAT-defective sterol-resistant hamster cells, J. Biol. Chem., 271, 14642, 10.1074/jbc.271.24.14642 · DOI
  10. Dahlquist, 1978, The meaning of Scatchard and Hill plots, Methods Enzymol., 48, 270, 10.1016/S0076-6879(78)48015-2 · DOI
  11. Engelking, 2005, Schoenheimer Effect explained—Feedback regulation of cholesterol synthesis in mice mediated by Insig proteins, J. Clin. Invest., 115, 2489, 10.1172/JCI25614 · DOI · Paper page
  12. Espenshade, 1999, Autocatalytic processing of Site-1 protease removes propeptide and permits cleavage of sterol regulatory element-binding proteins, J. Biol. Chem., 274, 22795, 10.1074/jbc.274.32.22795 · DOI · Paper page
  13. Goldstein, 1983, Receptor-mediated endocytosis of low density lipoprotein in cultured cells, Methods Enzymol., 98, 241, 10.1016/0076-6879(83)98152-1 · DOI
  14. Goldstein, 2006, Protein sensors for membrane sterols, Cell, 124, 35, 10.1016/j.cell.2005.12.022 · DOI · Paper page
  15. Green, 1987, Kinetics of intracellular transport and sorting of lysosomal membrane and plasma membrane proteins, J. Cell Biol., 105, 1227, 10.1083/jcb.105.3.1227 · DOI
  16. Kandutsch, 1974, Inhibition of sterol synthesis in cultured mouse cells by cholesterol derivatives oxygenated in the side chain, J. Biol. Chem., 249, 6057, 10.1016/S0021-9258(19)42218-7 · DOI · Paper page
  17. Koshland, 1966, Comparison of experimental binding data and theoretical models in proteins containing subunits, Biochemistry, 5, 365, 10.1021/bi00865a047 · DOI
  18. Kovanen, 1981, Saturation and suppression of hepatic lipoprotein receptors: A mechanism for the hypercholesterolemia of cholesterol-fed rabbits, Proc. Natl. Acad. Sci. USA, 78, l396, 10.1073/pnas.78.3.1396 · DOI
  19. Lange, 1997, Quantitation of the pool of cholesterol associated with acyl-CoA: Cholesterol acyltransferase in human fibroblasts, J. Biol. Chem., 272, 13103, 10.1074/jbc.272.20.13103 · DOI · Paper page
  20. Lange, 1999, Regulation of endoplasmic reticulum cholesterol by plasma membrane cholesterol, J. Lipid Res., 40, 2264, 10.1016/S0022-2275(20)32101-5 · DOI
  21. McDonald, 2007, Extraction and analysis of sterols in biological matrices by high performance liquid chromatography electrospray ionization mass spectrometry, Methods Enzymol., 432, 145, 10.1016/S0076-6879(07)32006-5 · DOI
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  27. Radhakrishnan, 2007, Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to Insig, Proc. Natl. Acad. Sci. USA, 104, 6511, 10.1073/pnas.0700899104 · DOI · Paper page
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Metadata

Authors
Radhakrishnan, A., Goldstein, J. L., McDonald, J. G., & Brown, M. S.
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2008-12
Volume
8
Issue
6
Pages
512-521
ISSN
1550-4131
DOI
10.1016/j.cmet.2008.10.008
PMC
PMC2652870
Cited by
534
References
2
Language
en
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