Cholesterol signaling

Cholesterol is a signaling molecule that is highly regulated in eukaryotic cell membranes.[1][2][3] In human health, its effects are most notable in inflammation and metabolic syndrome.[4] At the molecular level, cholesterol primarily signals by regulating lipid rafts[5] and raft associated membrane-protein translocation.

Mechanism

Lipid rafts are loosely defined as regions of lipid heterogeneity in cellular membranes.

Lipid raft regulation

Cholesterol regulates the function of several membrane proteins associated with lipid rafts. It does so by controlling the formation or depletion of lipid rafts in the plasma membrane. The lipid rafts house the membrane proteins and forming or depleting the lipid rafts moves the proteins in or out of the raft environment thereby exposing them to a new environment that can activate or deactivate the proteins. For example, cholesterol directly regulates the affinity of palmitoylated proteins for GM1 containing lipid rafts.[6] Cholesterol signaling through lipid rafts can be attenuated by phosphatidylinositol 4,5 bisphophate signaling (PIP2). PIP2 contains mostly polyunsaturated lipids that partition away from saturated lipids. Proteins that bind both lipid rafts and PIP2 are negatively regulated by high levels of PIP2. This effect was observed with phospholipase D.

Substrate presentation

A protein that is regulated by raft associated protein translocation can be activated by substrate presentation. For example, if an enzyme translocate in the membrane to its substrate it can be activated by localization to its substrate independent of a conformational change in the enzyme.[7]

Protein ligand

When cholesterol directly binds to a protein and alters its function it can be thought of as a protein ligand.

Ion channels

Cholesterol is thought to bind to cys loop receptors and allosterically modulate their gating.[8]

Role in Disease

Inflammation

During an inflammatory response cholesterol is loaded into immune cells including macrophages.[9] The cholesterol is a signal that activates cytokine production and other inflammatory responses.[10] Cholesterol's role in inflammation is central to many diseases.

Viral entry

Cholesterol loading into cells was recently shown to increase SARS-CoV-2 infectivity.[11]

Coronary Heart Disease

inflammation induced by cholesterol loading into immune cells causes heart disease. A class of drugs called statins blocks cholesterol synthesis and is used extensively in treating heart disease.

Steroids

Cholesterol is precursor for steroid hormones including progestagens, glucocorticoids, mineralocorticoids, androgens, and estrogens.[12]

History

Brown and Goldstein discovered the LDL receptor and showed cholesterol is loaded into cells through receptor mediated endocytosis.[13] Until recently cholesterol was thought of primarily as a structural component of the membrane. However, more recently, cholesterol uptake was shown to signal an immune response in macrophages. More importantly, the ability to efflux cholesterol through ABC transporters was shown to attenuate (i.e., shut down) the inflammatory response.[14]

References
  1. Wang, Hao; Kulas, Joshua A.; Ferris, Heather A.; Hansen, Scott B. (18 June 2020). "Regulation of amyloid processing in neurons by astrocyte-derived cholesterol". bioRxiv 10.1101/2020.06.18.159632.
  2. Liu, SL; Sheng, R; Jung, JH; Wang, L; Stec, E; O'Connor, MJ; Song, S; Bikkavilli, RK; Winn, RA; Lee, D; Baek, K; Ueda, K; Levitan, I; Kim, KP; Cho, W (March 2017). "Orthogonal lipid sensors identify transbilayer asymmetry of plasma membrane cholesterol". Nature Chemical Biology. 13 (3): 268–274. doi:10.1038/nchembio.2268. PMC 5912897. PMID 28024150.
  3. Jefcoate, CR; Lee, J (May 2018). "Cholesterol signaling in single cells: lessons from STAR and sm-FISH". Journal of Molecular Endocrinology. 60 (4): R213–R235. doi:10.1530/JME-17-0281. PMC 6324173. PMID 29691317.
  4. Eckel, RH; Grundy, SM; Zimmet, PZ (2005). "The metabolic syndrome". Lancet. 365 (9468): 1415–28. doi:10.1016/S0140-6736(05)66378-7. PMID 15836891. S2CID 27542682.
  5. Lingwood, D; Simons, K (1 January 2010). "Lipid rafts as a membrane-organizing principle". Science. 327 (5961): 46–50. Bibcode:2010Sci...327...46L. doi:10.1126/science.1174621. PMID 20044567.
  6. Levental, I; Lingwood, D; Grzybek, M; Coskun, U; Simons, K (21 December 2010). "Palmitoylation regulates raft affinity for the majority of integral raft proteins". Proceedings of the National Academy of Sciences of the United States of America. 107 (51): 22050–4. Bibcode:2010PNAS..10722050L. doi:10.1073/pnas.1016184107. PMC 3009825. PMID 21131568.
  7. Petersen, EN; Chung, HW; Nayebosadri, A; Hansen, SB (15 December 2016). "Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D." Nature Communications. 7: 13873. Bibcode:2016NatCo...713873P. doi:10.1038/ncomms13873. PMC 5171650. PMID 27976674.
  8. Levitan, I; Singh, DK; Rosenhouse-Dantsker, A (2014). "Cholesterol binding to ion channels". Frontiers in Physiology. 5: 65. doi:10.3389/fphys.2014.00065. PMC 3935357. PMID 24616704.
  9. Tall, Alan R.; Yvan-Charvet, Laurent (23 January 2015). "Cholesterol, inflammation and innate immunity". Nature Reviews Immunology. 15 (2): 104–116. doi:10.1038/nri3793. PMC 4669071. PMID 25614320.
  10. Fessler, Michael B.; Parks, John S. (15 August 2011). "Intracellular Lipid Flux and Membrane Microdomains as Organizing Principles in Inflammatory Cell Signaling". The Journal of Immunology. 187 (4): 1529–1535. doi:10.4049/jimmunol.1100253. PMC 3151145. PMID 21810617.
  11. Wang, Hao; Yuan, Zixuan; Pavel, Mahmud Arif; Hansen, Scott B. (29 May 2020). "The role of high cholesterol in age-related COVID19 lethality". bioRxiv 10.1101/2020.05.09.086249.
  12. Biochemistry (5th ed.). W.H. Freeman. ISBN 0-7167-3051-0.
  13. Goldstein, Joseph L.; Brown, Michael S. (April 2009). "The LDL Receptor". Arteriosclerosis, Thrombosis, and Vascular Biology. 29 (4): 431–438. doi:10.1161/ATVBAHA.108.179564. PMC 2740366. PMID 19299327.
  14. Tall, Alan R.; Yvan-Charvet, Laurent (23 January 2015). "Cholesterol, inflammation and innate immunity". Nature Reviews Immunology. 15 (2): 104–116. doi:10.1038/nri3793. PMC 4669071. PMID 25614320.
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