Biology:Cholesterol signaling

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Cholesterol is a cell signaling molecule that is highly regulated in eukaryotic cell membranes.[1][2][3] In human health, its effects are most notable in inflammation, metabolic syndrome, and neurodegeneration.[4] At the molecular level, cholesterol primarily signals by regulating clustering of saturated lipids[5] and proteins that depend on clustering for their regulation.

Cholesterol signaling (brain); Astrocyte cholesterol is exported to the neuron where it causes clustering of lipids. Clustering activates enzymes and other proteins by substrate presentation.[6]

Mechanism

Lipid rafts are loosely defined as clusters of cholesterol and saturated lipids forming regions of lipid heterogeneity in cellular membranes (e.g., the ganglioside GM1). The association of proteins to lipid rafts is cholesterol dependent and regulates the proteins' function (e.g., substrate presentation).

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.[7] Cholesterol signaling through lipid rafts can be attenuated by phosphatidylinositol 4,5 bisphosphate 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.

In the brain, astrocytes make the cholesterol and transport it to nerves to control their function. In this sense, cholesterol functions as a hormone.[8]

Substrate presentation

A protein subject to regulation through raft-associated translocation can undergo activation upon substrate presentation. For instance, an enzyme that translocates within the membrane towards its substrate can be activated by localizing to the substrate, irrespective of any conformational changes in the enzyme itself.[9]

Protein ligand

In addition to lipid rafts, cholesterol can also interact with proteins that possess lipid-binding domains, such as certain types of sterol-sensing domains or cholesterol recognition/interaction amino acid consensus (CRAC) motifs. These interactions can affect protein conformation, stability, and function, thereby influencing various cellular processes like signal transduction, membrane trafficking, and enzyme activity. As a signaling lipid, cholesterol may act as a ligand.

Ion channels

Numerous ion channels undergo palmitoylation, a lipid modification process.[10] Moreover, a significant subset of ion channels demonstrate a direct affinity for cholesterol binding.[11] The regulation of ion channels by cholesterol can stem from both direct binding interactions and an indirect influence, facilitated by the localization of palmitoylated residues within lipid rafts. It's important to note that these two mechanisms are not mutually exclusive; they can concurrently contribute to the modulation of ion channel activity and localization.

The spatial arrangement of an ion channel can profoundly impact its activation potential. Proposed mechanisms for this phenomenon encompass alterations in membrane thickness and the concentration of lipid molecules critical for signaling.[12] One instance of this is observed in TREK-1 channels, which transition between lipid rafts and PIP2 domains, where they interact with an activating lipid. Similarly, Kir2.1 channels experience inhibition due to cholesterol while being activated by PIP2. Consequently, a transition from cholesterol-enriched GM1 to PIP2-rich domains is anticipated to trigger channel activation.[13] Conversely, the scenario is opposite for nAChR, which responds positively to cholesterol, eliciting its activation. [14]

Role in Disease

Alzheimer's Disease

In the brain, cholesterol is synthesized in astrocytes and transported to neurons with the cholesterol transport protein apolipoprotein E (apoE). The cholesterol controls the clustering of amyloid precursor protein with gamma secretase in GM1 lipid domains.[15] High cholesterol induces APP hydrolysis and the eventual accumulation of amyloid plaques tau phosphorylation. The ApoE isotype4 is the greatest risk factor for sporadic Alzheimer's and this allele was shown to increase cholesterol in mice.[16]

Inflammation

Cholesterol uptake by cells instigates inflammation, affecting both the central nervous system and the peripheral systems.[17][18] This phenomenon involves the aggregation of inflammatory proteins. For instance, in the context of TLR4, cholesterol prompts receptor dimerization. Similarly, with TNF alpha, the substrate facilitates the enzyme's binding. Subsequent hydrolysis yields soluble cytokines, contributing to the inflammatory response.[19]


During an inflammatory response cholesterol is loaded into immune cells including macrophages.[20] The cholesterol is a signal that activates cytokine production and other inflammatory responses.[21] Cholesterol's role in inflammation is central to many diseases.

Viral entry

Numerous viruses exploit lipid rafts and endocytosis as entry pathways. Notably, SARS-CoV-2 has been demonstrated to leverage heightened cholesterol levels stemming from an immune response, thereby amplifying endocytosis and infectivity. Moreover, tissue cholesterol levels tend to rise with age. This augmented cholesterol presence provides insight into the greater severity of COVID-19 in elderly and chronically ill patients. [22]

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 progestogens, glucocorticoids, mineralocorticoids, androgens, and estrogens.[23]

History

Brown and Goldstein discovered the LDL receptor and showed cholesterol is loaded into cells through receptor mediated endocytosis.[24] 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.[25]

References

  1. ↑ Wang, Hao; Kulas, Joshua A.; Wang, Chao; Holtzman, David M.; Ferris, Heather A.; Hansen, Scott B. (17 August 2021). "Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol". Proceedings of the National Academy of Sciences 118 (33): e2102191118. doi:10.1073/pnas.2102191118. PMID 34385305. Bibcode: 2021PNAS..11802191W. 
  2. ↑ Liu, SL; Sheng, R; Jung, JH; Wang, L; Stec, E; O'Connor, MJ; Song, S; Bikkavilli, RK et al. (March 2017). "Orthogonal lipid sensors identify transbilayer asymmetry of plasma membrane cholesterol.". Nature Chemical Biology 13 (3): 268–274. doi:10.1038/nchembio.2268. 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. 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. 
  5. ↑ Lingwood, D; Simons, K (1 January 2010). "Lipid rafts as a membrane-organizing principle.". Science 327 (5961): 46–50. doi:10.1126/science.1174621. PMID 20044567. Bibcode: 2010Sci...327...46L. 
  6. ↑ Wang, Hao; Kulas, Joshua A.; Wang, Chao; Holtzman, David M.; Ferris, Heather A.; Hansen, Scott B. (17 August 2021). "Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol". Proceedings of the National Academy of Sciences 118 (33): e2102191118. doi:10.1073/pnas.2102191118. PMID 34385305. Bibcode: 2021PNAS..11802191W. 
  7. ↑ 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. doi:10.1073/pnas.1016184107. PMID 21131568. Bibcode: 2010PNAS..10722050L. 
  8. ↑ Wang, Hao; Kulas, Joshua A.; Wang, Chao; Holtzman, David M.; Ferris, Heather A.; Hansen, Scott B. (17 August 2021). "Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol". Proceedings of the National Academy of Sciences 118 (33): e2102191118. doi:10.1073/pnas.2102191118. PMID 34385305. Bibcode: 2021PNAS..11802191W. 
  9. ↑ 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. doi:10.1038/ncomms13873. PMID 27976674. Bibcode: 2016NatCo...713873P. 
  10. ↑ Shipston, Michael J. (March 2011). "Ion Channel Regulation by Protein Palmitoylation". Journal of Biological Chemistry 286 (11): 8709–8716. doi:10.1074/jbc.R110.210005. PMID 21216969. 
  11. ↑ Levitan, Irena; Singh, Dev K.; Rosenhouse-Dantsker, Avia (2014). "Cholesterol binding to ion channels". Frontiers in Physiology 5: 65. doi:10.3389/fphys.2014.00065. PMID 24616704. 
  12. ↑ Yuan, Zixuan; Hansen, Scott B. (20 February 2023). "Cholesterol Regulation of Membrane Proteins Revealed by Two-Color Super-Resolution Imaging". Membranes 13 (2): 250. doi:10.3390/membranes13020250. PMID 36837753. 
  13. ↑ Yuan, Zixuan; Hansen, Scott B. (20 February 2023). "Cholesterol Regulation of Membrane Proteins Revealed by Two-Color Super-Resolution Imaging". Membranes 13 (2): 250. doi:10.3390/membranes13020250. PMID 36837753. 
  14. ↑ Levitan, I; Singh, DK; Rosenhouse-Dantsker, A (2014). "Cholesterol binding to ion channels.". Frontiers in Physiology 5: 65. doi:10.3389/fphys.2014.00065. PMID 24616704. 
  15. ↑ Hansen, Scott B.; Wang, Hao (September 2023). "The shared role of cholesterol in neuronal and peripheral inflammation". Pharmacology & Therapeutics 249: 108486. doi:10.1016/j.pharmthera.2023.108486. PMID 37390970. 
  16. ↑ Wang, Hao; Kulas, Joshua A.; Wang, Chao; Holtzman, David M.; Ferris, Heather A.; Hansen, Scott B. (17 August 2021). "Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol". Proceedings of the National Academy of Sciences 118 (33): e2102191118. doi:10.1073/pnas.2102191118. PMID 34385305. Bibcode: 2021PNAS..11802191W. 
  17. ↑ 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. PMID 25614320. 
  18. ↑ Hansen, Scott B.; Wang, Hao (September 2023). "The shared role of cholesterol in neuronal and peripheral inflammation". Pharmacology & Therapeutics 249: 108486. doi:10.1016/j.pharmthera.2023.108486. PMID 37390970. 
  19. ↑ Hansen, Scott B.; Wang, Hao (September 2023). "The shared role of cholesterol in neuronal and peripheral inflammation". Pharmacology & Therapeutics 249: 108486. doi:10.1016/j.pharmthera.2023.108486. PMID 37390970. 
  20. ↑ 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. PMID 25614320. 
  21. ↑ 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. PMID 21810617. 
  22. ↑ Wang, Hao; Yuan, Zixuan; Pavel, Mahmud Arif; Jablonski, Sonia Mediouni; Jablonski, Joseph; Hobson, Robert; Valente, Susana; Reddy, Chakravarthy B. et al. (June 2023). "The role of high cholesterol in SARS-CoV-2 infectivity". Journal of Biological Chemistry 299 (6): 104763. doi:10.1016/j.jbc.2023.104763. PMID 37119851. 
  23. ↑ Biochemistry (5th ed.). W.H. Freeman. February 2002. ISBN 0-7167-3051-0. 
  24. ↑ 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. PMID 19299327. 
  25. ↑ 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. PMID 25614320. 



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