Editing CD36 (section)

== Clinical significance ==

=== Malaria ===

Infections with the human malaria parasite ''[[Plasmodium falciparum]]'' are characterized by sequestration of erythrocytes infected with mature forms of the parasite and CD36 has been shown to be a major sequestration receptor on [[microvascular]] endothelial cells. Parasitised erythrocytes adhere to endothelium at the [[trophozoite]]/[[wiktionary:schizont|schizonts]] stage simultaneous with the appearance of the ''var'' gene product (erythrocyte membrane protein 1) on the erythrocyte surface. The appearance of [[Plasmodium falciparum erythrocyte membrane protein 1|''Plasmodium falciparum'' erythrocyte membrane protein 1]] (PfEMP1) on the erythrocyte surface is a [[temperature]] dependent phenomenon which is due to increased protein trafficking to the erythrocyte surface at the raised temperature. PfEMP1 can bind other endothelial receptors - [[thrombospondin]] (TSP) and intercellular adhesion molecule 1 ([[ICAM-1]]) – in addition to CD36 - and genes other than PfEMP1 also bind to CD36: [[cytoadherence linked protein]] (clag) and [[sequestrin]]. The PfEMP1 binding site on CD36 is known to be located on exon 5.

CD36 on the surface of the platelets has been shown to be involved in adherence but direct adherence to the endothelium by the infected erythrocytes also occurs. Autoaggregation of infected erythrocytes by platelets has been shown to correlate with severe malaria and cerebral malaria in particular and antiplatelet antibodies may offer some protection.

Several lines of evidence suggest that mutations in CD36 are protective against malaria: mutations in the [[promoter (biology)|promoters]] and within introns and in exon 5 reduce the risk of severe malaria. Gene diversity studies suggest there has been positive selection on this gene presumably due to malarial selection pressure. Dissenting reports are also known 
suggesting that CD36 is not the sole determinant of severe malaria. In addition a role for CD36 has been found in the clearance of [[gametocyte]]s (stages I and II).

CD36 has been shown to have a role in the innate immune response to malaria in mouse models.<ref name="pmid17339496">{{cite journal | vauthors = Patel SN, Lu Z, Ayi K, Serghides L, Gowda DC, Kain KC | title = Disruption of CD36 impairs cytokine response to Plasmodium falciparum glycosylphosphatidylinositol and confers susceptibility to severe and fatal malaria in vivo | journal = Journal of Immunology | volume = 178 | issue = 6 | pages = 3954–61 | date = March 2007 | pmid = 17339496 | doi = 10.4049/jimmunol.178.6.3954 | doi-access = free }}</ref> Compared with wild type mice CD36 (-/-) mice the cytokine induction response and parasite clearance were impaired. Earlier peak parasitemias, higher parasite densities and higher mortality were noted. It is thought that CD36 is involved in the ''[[Plasmodium falciparum]]'' [[glycophosphatidylinositol]] (PfGPI) induced [[MAPK]] activation and proinflammatory cytokine secretion. When macrophages were exposed to PfGPI the proteins ERK1/2, JNK, p38, and c-Jun became phosphorylated. All these proteins are involved as secondary messengers in the immune response. These responses were blunted in the CD36 (-/-) mice. Also in the CD36 (-/-) macrophages secreted significantly less TNF-alpha on exposure to PfGPI. Work is ongoing to determine how these exactly how these responses provide protection against malaria.

=== CD36 deficiency and alloimmune thrombocytopenia ===

CD36 is also known as glycoprotein IV (gpIV) or glycoprotein IIIb (gpIIIb) in platelets and gives rise to the [[Naka antigen]]. The Naka null [[phenotype]] is found in 0.3% of Caucasians and appears to be asymptomatic. The null phenotype is more common in [[Africa]]n (2.5%), [[Japan]]ese, and other [[Asia]]n populations (5-11%).

Mutations in the human CD36 gene were first identified in a patient who, despite multiple [[platelet]] [[blood transfusions|transfusions]], continued to exhibit low platelet levels.<ref name="pmid2617957">{{cite journal | vauthors = Ikeda H, Mitani T, Ohnuma M, Haga H, Ohtzuka S, Kato T, Nakase T, Sekiguchi S | display-authors = 6 | title = A new platelet-specific antigen, Naka, involved in the refractoriness of HLA-matched platelet transfusion | journal = Vox Sanguinis | volume = 57 | issue = 3 | pages = 213–7 | year = 1989 | pmid = 2617957 | doi = 10.1111/j.1423-0410.1989.tb00826.x  |doi-access=free | s2cid = 39521299 }}</ref><ref name="pmid1699620">{{cite journal | vauthors = Yamamoto N, Ikeda H, Tandon NN, Herman J, Tomiyama Y, Mitani T, Sekiguchi S, Lipsky R, Kralisz U, Jamieson GA | display-authors = 6 | title = A platelet membrane glycoprotein (GP) deficiency in healthy blood donors: Naka- platelets lack detectable GPIV (CD36) | journal = Blood | volume = 76 | issue = 9 | pages = 1698–703 | date = November 1990 | pmid = 1699620 | doi = 10.1182/blood.V76.9.1698.1698 | url = http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=1699620 | doi-access = free | url-access = subscription }}</ref> This condition is known as refractoriness to platelet transfusion. Subsequent studies have shown that CD36 found on the surface of platelets. This antigen is recognized by the [[monoclonal antibodies]] (MAbs) OKM5 and OKM8. It is bound by the ''[[Plasmodium falciparum]]'' protein [[sequestrin]].<ref name="pmid1707534">{{cite journal | vauthors = Ockenhouse CF, Klotz FW, Tandon NN, Jamieson GA | title = Sequestrin, a CD36 recognition protein on Plasmodium falciparum malaria-infected erythrocytes identified by anti-idiotype antibodies | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 8 | pages = 3175–9 | date = April 1991 | pmid = 1707534 | pmc = 51408 | doi = 10.1073/pnas.88.8.3175 | bibcode = 1991PNAS...88.3175O | doi-access = free }}</ref>

Depending on the nature of the mutation in codon 90 CD36 may be absent either on both platelets and monocytes (type 1) or platelets alone (type 2). Type 2 has been divided into two subtypes - a and b. Deficiency restricted to the platelets alone is known as type 2a; if CD36 is also absent from the erythroblasts the phenotype is classified as type 2b.<ref name="pmid11602321">{{cite journal | vauthors = Toba K, Hanawa H, Watanabe K, Fuse I, Masuko M, Miyajima S, Takahashi M, Sakaue M, Abo T, Aizawa Y | display-authors = 6 | title = Erythroid involvement in CD36 deficiency | journal = Experimental Hematology | volume = 29 | issue = 10 | pages = 1194–200 | date = October 2001 | pmid = 11602321 | doi = 10.1016/S0301-472X(01)00691-9 | doi-access = free }}</ref> The molecular basis is known for some cases: T1264G in both [[Kenya]]ns and [[Gambia]]ns; C478T (50%), 539 deletion of AC and 1159 insertion of an A, 1438-1449 deletion and a combined 839-841 deletion GAG and insertion of AAAAC in Japanese.

In a study of 827 apparently healthy Japanese volunteers, type I and II deficiencies were found in 8 (1.0%) and 48 (5.8%) respectively.<ref name="pmid11019968">{{cite journal | vauthors = Yanai H, Chiba H, Fujiwara H, Morimoto M, Abe K, Yoshida S, Takahashi Y, Fuda H, Hui SP, Akita H, Kobayashi K, Matsuno K | display-authors = 6 | title = Phenotype-genotype correlation in CD36 deficiency types I and II | journal = Thrombosis and Haemostasis | volume = 84 | issue = 3 | pages = 436–41 | date = September 2000 | pmid = 11019968 | doi = 10.1055/s-0037-1614041 | s2cid = 42193140 }}</ref> In 1127 healthy French blood donors (almost all of whom were white Europeans) no CD36 deficiency was found.<ref name="pmid10504124">{{cite journal | vauthors = Lee K, Godeau B, Fromont P, Plonquet A, Debili N, Bachir D, Reviron D, Gourin J, Fernandez E, Galactéros F, Bierling P | display-authors = 6 | title = CD36 deficiency is frequent and can cause platelet immunization in Africans | journal = Transfusion | volume = 39 | issue = 8 | pages = 873–9 | date = August 1999 | pmid = 10504124 | doi = 10.1046/j.1537-2995.1999.39080873.x | s2cid = 21921171 | doi-access = free }}</ref> In a second group only 1 of 301 white test subjects was found to be CD36 deficient. 16 of the 206 sub-Saharan black Africans and 1 of 148 black Caribbeans were found to be CD36 -ve. Three of 13 CD36 -ve persons examined had anti CD36 antibodies. In a group of 250 black American blood donors 6 (2.4%) were found to be Naka antigen negative.<ref name="pmid8623134">{{cite journal | vauthors = Curtis BR, Aster RH | title = Incidence of the Nak(a)-negative platelet phenotype in African Americans is similar to that of Asians | journal = Transfusion | volume = 36 | issue = 4 | pages = 331–4 | date = April 1996 | pmid = 8623134 | doi = 10.1046/j.1537-2995.1996.36496226147.x | s2cid = 10991605 }}</ref>

CD36 deficiency may be a cause of post transfusion [[purpura]].<ref name="pmid7570941">{{cite journal | vauthors = Bierling P, Godeau B, Fromont P, Bettaieb A, Debili N, el-Kassar N, Rouby JJ, Vainchenker W, Duedari N | display-authors = 6 | title = Posttransfusion purpura-like syndrome associated with CD36 (Naka) isoimmunization | journal = Transfusion | volume = 35 | issue = 9 | pages = 777–82 | date = September 1995 | pmid = 7570941 | doi = 10.1046/j.1537-2995.1995.35996029165.x | s2cid = 22706156 }}</ref>

=== Blood pressure ===
Below normal levels of CD36 expression in the kidneys has been implicated as a genetic risk factor for [[hypertension]] (high blood pressure).<ref name="pmid18587397">{{cite journal | vauthors = Pravenec M, Churchill PC, Churchill MC, Viklicky O, Kazdova L, Aitman TJ, Petretto E, Hubner N, Wallace CA, Zimdahl H, Zidek V, Landa V, Dunbar J, Bidani A, Griffin K, Qi N, Maxova M, Kren V, Mlejnek P, Wang J, Kurtz TW | display-authors = 6 | title = Identification of renal Cd36 as a determinant of blood pressure and risk for hypertension | journal = Nature Genetics | volume = 40 | issue = 8 | pages = 952–4 | date = August 2008 | pmid = 18587397 | doi = 10.1038/ng.164 | s2cid = 6857655 }}</ref>

=== Fatty acid uptake ===

An association with myocardial fatty acid uptake in humans has been noted.<ref name="pmid9707006">{{cite journal | vauthors = Okamoto F, Tanaka T, Sohmiya K, Kawamura K | title = CD36 abnormality and impaired myocardial long-chain fatty acid uptake in patients with hypertrophic cardiomyopathy | journal = Japanese Circulation Journal | volume = 62 | issue = 7 | pages = 499–504 | date = July 1998 | pmid = 9707006 | doi = 10.1253/jcj.62.499 | doi-access = free }}</ref> The data suggest a link between [[hypertrophic cardiomyopathy]] and CD36 but this needs to be confirmed.

=== Tuberculosis ===

[[RNAi]] screening in a ''[[Drosophila]]'' model has revealed that a member of the CD36 family is required for [[phagocytosis]] of ''[[Mycobacterium tuberculosis]]'' into macrophage phagosomes.<ref name="pmid16020694">{{cite journal | vauthors = Philips JA, Rubin EJ, Perrimon N | s2cid = 26751583 | title = Drosophila RNAi screen reveals CD36 family member required for mycobacterial infection | journal = Science | volume = 309 | issue = 5738 | pages = 1251–3 | date = August 2005 | pmid = 16020694 | doi = 10.1126/science.1116006 | bibcode = 2005Sci...309.1251P | doi-access = free }}</ref>

=== Toxoplasmosis ===

Avirulent strains of ''[[Toxoplasma gondii]]'' bind to CD36 but virulent parasites fail to engage CD36. In mice, CD36 is required for disease tolerance but not for the development of immunity or resistance.<ref name="pmid34400524">{{cite journal | vauthors = Zhao Y, Reyes, J, Rovira-Diaz E, Fox BA, Bzik D, Yap GS | title = CD36 mediates phagocyte tropism and avirulence of Toxoplasma gondii | journal = Journal of Immunology |date = August 2021 | volume = 207 | issue = 6 | pages = 1507–1512 | pmid = 34400524 | doi = 10.4049/jimmunol.2100605 | issn=0022-1767 | pmc = 8429199 | s2cid = 237148810 }}</ref>

=== Obesity ===

CD36's association with the ability to [[taste]] fats has made it a target for various studies regarding [[obesity]] and alteration of [[lipid]] [[taste|tasting]]. CD36 mRNA expression was found to be reduced in [[taste bud]] cells (TBC) of obese [[sand rat]]s (''P. obesus'') compared to lean controls, implicating an association between CD36 and obesity.<ref name="Abdoul-Azize S, Atek-Mebarki F, Bitam A, Sadou H, Koceïr EA, Khan NA 2013 e68532">{{cite journal | vauthors = Abdoul-Azize S, Atek-Mebarki F, Bitam A, Sadou H, Koceïr EA, Khan NA | title = Oro-gustatory perception of dietary lipids and calcium signaling in taste bud cells are altered in nutritionally obesity-prone Psammomys obesus | journal = PLOS ONE | volume = 8 | issue = 8 | pages = e68532 | year = 2013 | pmid = 23936306 | pmc = 3731325 | doi = 10.1371/journal.pone.0068532 | bibcode = 2013PLoSO...868532A | doi-access = free }}</ref> Although actual levels of CD36 protein were not different between the obese and control rat cells, Abdoul-Azize et al. hypothesize that the physical distribution of CD36 could differ in obese rat cells.<ref name="Abdoul-Azize S, Atek-Mebarki F, Bitam A, Sadou H, Koceïr EA, Khan NA 2013 e68532"/> Changes in calcium mediation have been associated with CD36 and obesity as well. Taste bud cells (more specifically, cells from the [[lingual papilla|circumvallate papillae]]) containing CD36 that were isolated from obese mice exhibited a significantly smaller increase in calcium after fatty acid stimulation when compared to control mice:<ref name="Chevrot M, Bernard A, Ancel D, Buttet M, Martin C, Abdoul-Azize S, Merlin JF, Poirier H, Niot I, Khan NA, Passilly-Degrace P, Besnard P 2013 2485–94">{{cite journal | vauthors = Chevrot M, Bernard A, Ancel D, Buttet M, Martin C, Abdoul-Azize S, Merlin JF, Poirier H, Niot I, Khan NA, Passilly-Degrace P, Besnard P | display-authors = 6 | title = Obesity alters the gustatory perception of lipids in the mouse: plausible involvement of lingual CD36 | journal = Journal of Lipid Research | volume = 54 | issue = 9 | pages = 2485–94 | date = September 2013 | pmid = 23840049 | pmc = 3735945 | doi = 10.1194/jlr.M039446  |doi-access=free }}</ref> CD36 associated calcium regulation is impaired when mice are made to be obese (but not in normal weight mice), and this could be a mechanism contributing to behavior changes in the obese mice, such as decreased lipid taste sensitivity and decreased attraction to fats.<ref name="Chevrot M, Bernard A, Ancel D, Buttet M, Martin C, Abdoul-Azize S, Merlin JF, Poirier H, Niot I, Khan NA, Passilly-Degrace P, Besnard P 2013 2485–94"/>

There has been some investigation into human CD36 as well. A study examined oral detection of fat in obese subjects with genetic bases for high, medium, and low expression of the CD36 receptor. Those subjects with high CD36 expression were eight times more sensitive to certain fats ([[oleic acid]] and [[triolein]]) than the subjects with low CD36 expression.<ref name="Pepino_2012"/> Those subjects with an intermediate amount of CD36 expression were sensitive to fat at a level between the high and low groups.<ref name="Pepino_2012"/> This study demonstrates that there is a significant relationship between oral fat sensitivity and the amount of CD36 receptor expression, but further investigation into CD36 could be useful for learning more about lipid tasting in the context of obesity, as CD36 may be a target for therapies in the future.

=== Establishment of cellular senescence ===

Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice.<ref>{{cite journal | vauthors = Moiseeva V | display-authors = etal | year = 2022 | title = Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration | journal = Nature | volume = 612| issue = 7941| pages = 169–178 | doi = 10.1038/s41586-022-05535-x | pmid = 36544018| pmc = 9812788}}{{Creative Commons text attribution notice|cc=by3|from this source=yes}}</ref>