Editing Cholesterol (section)

===Function===

====Membranes====
Cholesterol is present in varying degrees in all animal [[cell membrane]]s, but is absent in prokaryotes.<ref>{{cite book | title = Biochemistry | edition = 7th | vauthors = Berg JM, Tymoczko JL, Stryer L | date = 2010 | page = 350 }}</ref> It is required to build and maintain membranes and modulates [[membrane fluidity]] over the range of physiological temperatures. The [[hydroxyl]] group of each cholesterol molecule interacts with water molecules surrounding the membrane, as do the [[Polar molecules|polar]] heads of the [[lipid bilayer|membrane]] [[phospholipid]]s and [[sphingolipid]]s, while the bulky [[steroid]] and the [[hydrocarbon]] chain are embedded in the membrane, alongside the [[Polar molecules#Nonpolar molecules|nonpolar]] [[Fatty acid|fatty-acid chain]] of the other lipids. Through the interaction with the phospholipid fatty-acid chains, cholesterol increases membrane packing, which both alters membrane fluidity<ref name="isbn1-4292-4646-4">{{cite book |vauthors=Sadava D, Hillis DM, Heller HC, Berenbaum MR | chapter = Cell Membranes | title = Life: The Science of Biology | edition = 9th | publisher = Freeman | location = San Francisco | year = 2011 | pages = 105–114 | isbn = 978-1-4292-4646-0 }}</ref> and maintains membrane integrity so that animal cells do not need to build cell walls (like plants and most bacteria). The membrane remains stable and durable without being rigid, allowing animal cells to change shape and animals to move.{{cn|date=December 2024}}

The structure of the [[tetracyclic]] ring of cholesterol contributes to the fluidity of the cell membrane, as the molecule is in a ''trans'' conformation making all but the side chain of cholesterol rigid and planar.<ref name="Ohvo-Rekilä_2002">{{cite journal | vauthors = Ohvo-Rekilä H, Ramstedt B, Leppimäki P, Slotte JP | title = Cholesterol interactions with phospholipids in membranes | journal = Progress in Lipid Research | volume = 41 | issue = 1 | pages = 66–97 | date = January 2002 | pmid = 11694269 | doi = 10.1016/S0163-7827(01)00020-0 }}</ref> In this structural role, cholesterol also reduces the permeability of the plasma membrane to neutral solutes,<ref name="Yeagle_1991">{{cite journal | vauthors = Yeagle PL | title = Modulation of membrane function by cholesterol | journal = Biochimie | volume = 73 | issue = 10 | pages = 1303–1310 | date = October 1991 | pmid = 1664240 | doi = 10.1016/0300-9084(91)90093-G }}</ref> [[hydrogen]] ions, and [[sodium]] ions.<ref name="Haines_2001">{{cite journal | vauthors = Haines TH | title = Do sterols reduce proton and sodium leaks through lipid bilayers? | journal = Progress in Lipid Research | volume = 40 | issue = 4 | pages = 299–324 | date = July 2001 | pmid = 11412894 | doi = 10.1016/S0163-7827(01)00009-1 | s2cid = 32236169 }}</ref>

====Substrate presentation====
Cholesterol regulates the biological process of [[substrate presentation]] and the enzymes that use substrate presentation as a mechanism of their activation. Phospholipase D2 ([[PLD2]]) is a well-defined example of an enzyme activated by substrate presentation.<ref>{{cite journal | vauthors = Petersen EN, Chung HW, Nayebosadri A, Hansen SB | title = Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D | journal = Nature Communications | volume = 7 | pages = 13873 | date = December 2016 | pmid = 27976674 | pmc = 5171650 | doi = 10.1038/ncomms13873 | bibcode = 2016NatCo...713873P }}</ref> The enzyme is [[palmitoylation|palmitoylated]] causing the enzyme to traffic to cholesterol dependent lipid domains sometimes called "[[lipid rafts]]". The substrate of [[phospholipase D]] is [[phosphatidylcholine]] (PC) which is unsaturated and is of low abundance in lipid rafts. PC localizes to the disordered region of the cell along with the polyunsaturated lipid [[phosphatidylinositol 4,5-bisphosphate]] (PIP2). PLD2 has a PIP2 [[binding domain]]. When PIP2 concentration in the membrane increases, PLD2 leaves the cholesterol-dependent domains and binds to PIP2 where it then gains access to its substrate PC and commences catalysis based on substrate presentation.{{cn|date=December 2024}}
[[File:Enzyme translocation.png|thumb|right|upright=2|'''[[Substrate presentation]]'''; PLD (blue oval) is sequestered into cholesterol-dependent lipid domains (green lipids) by [[palmitoylation]]. PLD also binds PIP2(red hexagon) domains (grey shading) located in the disordered region of the cell with phosphatidylcholine (PC). When cholesterol decreases or PIP2 increases in the cell, PLD translocates to PIP2 where it is exposed to and hydrolizes PC to phosphatidic acid (red spherical lipid).]]

====Signaling====
{{Main|Cholesterol signaling}}

Cholesterol is also implicated in cell signaling processes, assisting in the formation of [[lipid raft]]s in the [[plasma membrane]], which brings receptor proteins in close proximity with high concentrations of second messenger molecules.<ref name="Incardona_2000">{{cite journal | vauthors = Incardona JP, Eaton S | title = Cholesterol in signal transduction | journal = Current Opinion in Cell Biology | volume = 12 | issue = 2 | pages = 193–203 | date = April 2000 | pmid = 10712926 | doi = 10.1016/S0955-0674(99)00076-9 }}
</ref> In multiple layers, cholesterol and phospholipids, both electrical insulators, can facilitate speed of transmission of electrical impulses along nerve tissue. For many neuron fibers, a [[myelin]] sheath, rich in cholesterol since it is derived from compacted layers of [[Schwann cell]] or oligodendrocyte membranes, provides insulation for more efficient conduction of impulses.<ref name="isbn0-7817-5056-3">{{cite book |vauthors=Pawlina W, Ross MW | chapter = Supporting Cells of the Nervous System | title = Histology: a text and atlas: with correlated cell and molecular biology | edition = 5th | publisher = Lippincott Williams & Wilkins | location = Philadelphia | year = 2006 | pages = 339 | isbn = 978-0-7817-5056-1 }}</ref> [[Demyelination]] (loss of myelin) is believed to be part of the basis for [[multiple sclerosis]].{{cn|date=December 2024}}

Cholesterol binds to and affects the gating of a number of [[ion channel]]s such as the [[nicotinic acetylcholine receptor]], [[GABAA receptor|GABA<sub>A</sub> receptor]], and the [[inward-rectifier potassium channel]].<ref name="LevitanSingh2014">{{cite journal | vauthors = Levitan I, Singh DK, Rosenhouse-Dantsker A | title = Cholesterol binding to ion channels | journal = Frontiers in Physiology | volume = 5 | pages = 65 | year = 2014 | pmid = 24616704 | pmc = 3935357 | doi = 10.3389/fphys.2014.00065 | doi-access = free }}</ref> Cholesterol also activates the [[estrogen-related receptor alpha]] (ERRα), and may be the [[Endogeny (biology)|endogenous]] [[ligand (biochemistry)|ligand]] for the [[receptor (biochemistry)|receptor]].<ref name="WeiSchwaid2016">{{cite journal | vauthors = Wei W, Schwaid AG, Wang X, Wang X, Chen S, Chu Q, Saghatelian A, Wan Y | title = Ligand Activation of ERRα by Cholesterol Mediates Statin and Bisphosphonate Effects | journal = Cell Metabolism | volume = 23 | issue = 3 | pages = 479–491 | date = March 2016 | pmid = 26777690 | pmc = 4785078 | doi = 10.1016/j.cmet.2015.12.010 }}</ref><ref name="Elsevier2017">{{cite book | vauthors = Zuo H, Wan Y | chapter = Nuclear Receptors in Skeletal Homeostasis | veditors = Forrest D, Tsai S |title=Nuclear Receptors in Development and Disease| chapter-url = https://books.google.com/books?id=ZvupDQAAQBAJ&pg=PA88 |year=2017|publisher=Elsevier Science|isbn=978-0-12-802196-5|pages=88 }}</ref> The constitutively active nature of the receptor may be explained by the fact that cholesterol is ubiquitous in the body.<ref name="Elsevier2017" /> Inhibition of ERRα signaling by reduction of cholesterol production has been identified as a key mediator of the effects of [[statin]]s and [[bisphosphonate]]s on [[bone]], [[muscle]], and [[macrophage]]s.<ref name="WeiSchwaid2016" /><ref name="Elsevier2017" /> On the basis of these findings, it has been suggested that the ERRα should be de-orphanized and classified as a receptor for cholesterol.<ref name="WeiSchwaid2016" /><ref name="Elsevier2017" />

==== As a chemical precursor ====
Within cells, cholesterol is also a precursor molecule for several [[Metabolic pathway|biochemical pathway]]s. For example, it is the precursor molecule for the synthesis of [[vitamin D]] in the [[calcium metabolism]] and all [[steroid hormones]], including the [[adrenal gland]] hormones [[cortisol]] and [[aldosterone]], as well as the sex hormones [[progesterone]], [[estrogen]]s, and [[testosterone]], and their derivatives.<ref name="Hanukoglu_1992" /><ref name="Payne_2004">{{cite journal | vauthors = Payne AH, Hales DB | title = Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones | journal = Endocrine Reviews | volume = 25 | issue = 6 | pages = 947–70 | date = December 2004 | pmid = 15583024 | doi = 10.1210/er.2003-0030 | doi-access = free }}</ref>

====Epidermis====
The stratum corneum is the outermost layer of the epidermis.<ref name="Elias-2006">{{cite book | vauthors = Elias PM, Feingold KR | chapter = Stratum Corneum Barrier Function: Definitions and Broad Concepts | veditors = Elias PM |title=Skin barrier |date=2006 |publisher=Taylor & Francis |location=New York |isbn=978-0824758158}}</ref><ref name="Merleev et al-2022" /> It is composed of terminally differentiated and enucleated [[corneocyte]]s that reside within a lipid matrix, like "bricks and mortar."<ref name="Elias-2006" /><ref name="Merleev et al-2022">{{cite journal | vauthors = Merleev AA, Le ST, Alexanian C, Toussi A, Xie Y, Marusina AI, Watkins SM, Patel F, Billi AC, Wiedemann J, Izumiya Y, Kumar A, Uppala R, Kahlenberg JM, Liu FT, Adamopoulos IE, Wang EA, Ma C, Cheng MY, Xiong H, Kirane A, Luxardi G, Andersen B, Tsoi LC, Lebrilla CB, Gudjonsson JE, Maverakis E | title = Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes | journal = JCI Insight | volume = 7 | issue = 16 | date = August 2022 | pmid = 35900871 | pmc = 9462509 | doi = 10.1172/jci.insight.159762 }}</ref> Together with [[ceramide]]s and free fatty acids, cholesterol forms the lipid mortar, a water-impermeable barrier that prevents evaporative water loss. As a rule of thumb, the epidermal lipid matrix is composed of an equimolar mixture of ceramides (≈50% by weight), cholesterol (≈25% by weight), and free fatty acids (≈15% by weight), with smaller quantities of other lipids also being present.<ref name="Elias-2006" /><ref name="Merleev et al-2022" /> Cholesterol sulfate reaches its highest concentration in the granular layer of the epidermis. Steroid sulfate sulfatase then decreases its concentration in the stratum corneum, the outermost layer of the epidermis.<ref>{{cite journal | vauthors = Elias PM, Williams ML, Maloney ME, Bonifas JA, Brown BE, Grayson S, Epstein EH | title = Stratum corneum lipids in disorders of cornification. Steroid sulfatase and cholesterol sulfate in normal desquamation and the pathogenesis of recessive X-linked ichthyosis | journal = The Journal of Clinical Investigation | volume = 74 | issue = 4 | pages = 1414–1421 | date = October 1984 | pmid = 6592175 | pmc = 425309 | doi = 10.1172/JCI111552 }}</ref> The relative abundance of cholesterol sulfate in the epidermis varies across different body sites with the heel of the foot having the lowest concentration.<ref name="Merleev et al-2022" />