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.

Contents

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. Cholesterol signaling in the brain..png
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.

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]

Related Research Articles

<span class="mw-page-title-main">Cholesterol</span> Sterol biosynthesized by all animal cells

Cholesterol is the principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.

<span class="mw-page-title-main">Lipid-anchored protein</span> Membrane protein

Lipid-anchored proteins are proteins located on the surface of the cell membrane that are covalently attached to lipids embedded within the cell membrane. These proteins insert and assume a place in the bilayer structure of the membrane alongside the similar fatty acid tails. The lipid-anchored protein can be located on either side of the cell membrane. Thus, the lipid serves to anchor the protein to the cell membrane. They are a type of proteolipids.

<span class="mw-page-title-main">Lipid raft</span>

The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains somewhat controversial. It has been proposed that they are specialized membrane microdomains which compartmentalize cellular processes by serving as organising centers for the assembly of signaling molecules, allowing a closer interaction of protein receptors and their effectors to promote kinetically favorable interactions necessary for the signal transduction. Lipid rafts influence membrane fluidity and membrane protein trafficking, thereby regulating neurotransmission and receptor trafficking. Lipid rafts are more ordered and tightly packed than the surrounding bilayer, but float freely within the membrane bilayer. Although more common in the cell membrane, lipid rafts have also been reported in other parts of the cell, such as the Golgi apparatus and lysosomes.

<span class="mw-page-title-main">Astrogliosis</span> Increase in astrocytes in response to brain injury

Astrogliosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease. In healthy neural tissue, astrocytes play critical roles in energy provision, regulation of blood flow, homeostasis of extracellular fluid, homeostasis of ions and transmitters, regulation of synapse function and synaptic remodeling. Astrogliosis changes the molecular expression and morphology of astrocytes, in response to infection for example, in severe cases causing glial scar formation that may inhibit axon regeneration.

Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty acids. They constitute about 0.25% of phospholipids in the bilayer.

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Phosphoinositide phospholipase C</span>

Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. These enzymes belong to a larger superfamily of Phospholipase C. Other families of phospholipase C enzymes have been identified in bacteria and trypanosomes. Phospholipases C are phosphodiesterases.

<span class="mw-page-title-main">Phosphatidylinositol 4,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)P2 is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins. PIP2 also forms lipid clusters that sort proteins.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an enzyme of the phospholipase superfamily that catalyses the following reaction

<span class="mw-page-title-main">Palmitoylation</span>

Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (S-palmitoylation) and less frequently to serine and threonine (O-palmitoylation) residues of proteins, which are typically membrane proteins. The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their membrane association. Palmitoylation also appears to play a significant role in subcellular trafficking of proteins between membrane compartments, as well as in modulating protein–protein interactions. In contrast to prenylation and myristoylation, palmitoylation is usually reversible (because the bond between palmitic acid and protein is often a thioester bond). The reverse reaction in mammalian cells is catalyzed by acyl-protein thioesterases (APTs) in the cytosol and palmitoyl protein thioesterases in lysosomes. Because palmitoylation is a dynamic, post-translational process, it is believed to be employed by the cell to alter the subcellular localization, protein–protein interactions, or binding capacities of a protein.

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. Fatty acid metabolites with affinity for this receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA). The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). In primary afferent sensory neurons, it cooperates with TRPA1 to mediate the detection of noxious environmental stimuli.

<span class="mw-page-title-main">Phospholipase C</span> Class of enzymes

Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role in eukaryotic cell physiology, in particular signal transduction pathways. Phospholipase C's role in signal transduction is its cleavage of phosphatidylinositol 4,5-bisphosphate (PIP2) into diacyl glycerol (DAG) and inositol 1,4,5-trisphosphate (IP3), which serve as second messengers. Activators of each PLC vary, but typically include heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca2+, and phospholipids.

The G protein-coupled inwardly rectifying potassium channels (GIRKs) are a family of lipid-gated inward-rectifier potassium ion channels which are activated (opened) by the signaling lipid PIP2 and a signal transduction cascade starting with ligand-stimulated G protein-coupled receptors (GPCRs). GPCRs in turn release activated G-protein βγ- subunits (Gβγ) from inactive heterotrimeric G protein complexes (Gαβγ). Finally, the Gβγ dimeric protein interacts with GIRK channels to open them so that they become permeable to potassium ions, resulting in hyperpolarization of the cell membrane. G protein-coupled inwardly rectifying potassium channels are a type of G protein-gated ion channels because of this direct interaction of G protein subunits with GIRK channels. The activation likely works by increasing the affinity of the channel for PIP2. In high concentration PIP2 activates the channel absent G-protein, but G-protein does not activate the channel absent PIP2.

<span class="mw-page-title-main">Type 3 diabetes</span> Medical condition

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<span class="mw-page-title-main">Lipid-gated ion channels</span> Type of ion channel transmembrane protein

Lipid-gated ion channels are a class of ion channels whose conductance of ions through the membrane depends directly on lipids. Classically the lipids are membrane resident anionic signaling lipids that bind to the transmembrane domain on the inner leaflet of the plasma membrane with properties of a classic ligand. Other classes of lipid-gated channels include the mechanosensitive ion channels that respond to lipid tension, thickness, and hydrophobic mismatch. A lipid ligand differs from a lipid cofactor in that a ligand derives its function by dissociating from the channel while a cofactor typically derives its function by remaining bound.

Substrate presentation is a biological process that activates a protein. The protein is sequestered away from its substrate and then activated by release and exposure of the protein to its substrate. A substrate is typically the substance on which an enzyme acts but can also be a protein surface to which a ligand binds. The substrate is the material acted upon. In the case of an interaction with an enzyme, the protein or organic substrate typically changes chemical form. Substrate presentation differs from allosteric regulation in that the enzyme need not change its conformation to begin catalysis. Substrate presentation is best described for nanoscopic distances (<100 nm).

PIP2 domains are a type of cholesterol-independent lipid domain formed from phosphatidylinositol and positively charged proteins in the plasma membrane. They tend to inhibit GM1 lipid raft function.

Membrane-mediated anesthesia or anaesthesia (UK) is a mechanism of action that involves an anesthetic exerting its effects through the lipid membrane. Established mechanism exists for both general and local anesthetics. The anesthetic binding site is within ordered lipids and binding disrupts the function of the ordered lipid. See Theories of general anaesthetic action for a broader discussion of purely theoretical mechanisms.

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. Bibcode:2021PNAS..11802191W. doi: 10.1073/pnas.2102191118 . PMC   8379952 . PMID   34385305.
  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. S2CID   35095032.
  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. Bibcode:2021PNAS..11802191W. doi: 10.1073/pnas.2102191118 . PMC   8379952 . PMID   34385305.
  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. Bibcode:2010PNAS..10722050L. doi: 10.1073/pnas.1016184107 . PMC   3009825 . PMID   21131568.
  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. Bibcode:2021PNAS..11802191W. doi: 10.1073/pnas.2102191118 . PMC   8379952 . PMID   34385305.
  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. Bibcode:2016NatCo...713873P. doi:10.1038/ncomms13873. PMC   5171650 . PMID   27976674.
  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 . PMC   3058972 . 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 . PMC   3935357 . 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 . PMC   9966874 . 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 . PMC   9966874 . 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 . PMC   3935357 . 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. S2CID   259303593.
  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. Bibcode:2021PNAS..11802191W. doi: 10.1073/pnas.2102191118 . PMC   8379952 . PMID   34385305.
  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. PMC   4669071 . 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. S2CID   259303593.
  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. S2CID   259303593.
  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. PMC   4669071 . 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. PMC   3151145 . PMID   21810617.
  22. ↑ Wang, Hao; Yuan, Zixuan; Pavel, Mahmud Arif; Jablonski, Sonia Mediouni; Jablonski, Joseph; Hobson, Robert; Valente, Susana; Reddy, Chakravarthy B.; Hansen, Scott B. (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 . PMC   10140059 . 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. PMC   2740366 . 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. PMC   4669071 . PMID   25614320.
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