Apolipoprotein E
Apolipoprotein E (APOE) je protein uključen u metabolizam masti u tijelu sisara. Podtip je uključen u Alzheimerovu i kardiovaskularne bolesti.[5]
APOE pripada porodici proteina koji vežu masti, pod nazivom apolipoproteini. U cirkulaciji je prisutan kao dio nekoliko klasa lipoproteinskih čestica, uključujući ostatke hilomikrona, VLDL, IDL i neke HDL.[6] APOE značajno komunicira sa lipoproteinskim receptorom male gustoće (LDLR), što je neophodno za normalnu preradu (katabolizam) lipoproteina bogatih trigliceridima.[7] U perifernim tkivima primarno ga proizvode jetra i makrofagi i posreduje u metabolizmu holesterola. U centralnom nervnom sistemu, APOE uglavnom proizvode astrociti i transportuje holesterol u neurone[8] putem APOE receptora, koji su članovi porodice gena lipoproteinskih receptora male gustoće.[9] APOE je glavni nositelj holesterola u mozgu.[10] APOE je potreban za transport holesterola iz astrocita u neurone.[8] Kvalificira se kao inhibitor kontrolne tačke klasičnog puta komplementa, formiranjem kompleksa sa aktiviranim C1q.[11]
Evolucija
urediApolipoproteini nisu jedinstveni za sisare. Mnogi kopneni i morski kičmenjaci imaju svoje verzije.[12] Proteini slične funkcije pronađeni su u hoanoflagelatama, što upućuje na to da su oni vrlo stara klasa proteina koji prethode zori svih živih životinja. Smatra se da je APOE nastao duplikacijom gena APOC-I, prije nego što su se sisari i ribe podijelili, prije 400 miliona godina.[13]
Tri glavna ljudska alela (E4, E3, E2) nastala su nakon razdvajanja ostalih primata i čovjeka, prije oko 7,5 miliona godina. Ovi aleli su nusprodukt nesinonimnih mutacija koje su dovele do promjena u funkcionalnosti. Prvi alel koji se pojavio bio je E4. Nakon razdvajanja primata i čovjeka, dogodile su se četiri aminokiselinske promjene u ljudskoj lozi, od kojih tri nisu uticale na funkciju proteina (V174L, A18T, A135V). Četvrta supstitucija zamjenjuje treonin za arginin, koji mijenja funkcionalnost proteina. Ova supstitucija dogodila se negdje u razmaku od oko šest miliona godina između razdvajanja primata i čovjeka i razdvajanja Denisovskih ljudi, jer su potpuno iste zamjene pronađene u Denisovskom APOE.[14]
Prije oko 220.000 godina, dogodila se supstitucija arginina u cistein u aminokiselini 112 (Arg112Cys) gena APOE4, što je rezultiralo alelom E3. Konačno, prije 80.000 godina, druga supstitucija arginina u cistein na aminokiselini 158 (Arg158Cys) gena APOE3 stvorila je alel E2.[13][15]
Struktura
urediGen
urediGen, APOE , mapiran je na hromosomu 19 u klasteru sa apoliproteinom C1 (APOC1) i apolipoproteinom C2 (APOC2). Gen APOE sastoji se od četiri egzona i tri introna, što ukupno iznosi 3.597 baznih parova. APOE transkripcijski aktiviraju jetreni X receptor (važan regulator homeostaza holesterola, masnih kiselina i glukoze) i receptor aktiviran proliferatorom peroksizoma γ, jedarni receptor koji tvore heterodimere sa retinoidnim X receptorima.[16] U melanocitnim ćelijama ekspresija gena APOE može se regulirati pomoću transkripcijskog faktora povezanog sa mikroftalmijom ( MITF).[17]
Protein
urediAPOE je dugačak 299 aminokiselina i sadrži višestruke amfipatijske α-helikse. Prema studijama kristalografije, zglobna regija povezuje regije N– i C-kraja proteina. N-terminalno područje (ostaci 1–167) tvori antiparalelni snop od četiri zavojnice, tako da su nepolarne strane okrenute unutar proteina. U međuvremenu, C-terminalni domen (ostaci 206–299) sadrži tri α-heliksa koji čine veliku izloženu hidrofob nu površinu i u interakciji s onima u N-terminalnom domenu spirale vodikovih veza i mostova soli. C-terminalna regija takođe sadrži mjesto vezanja lipoproteinskog receptora male gustoće (LDLR).[18]
- Aminokiselinska sekvenca
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MKVLWAALLV | TFLAGCQAKV | EQAVETEPEP | ELRQQTEWQS | GQRWELALGR | ||||
| FWDYLRWVQT | LSEQVQEELL | SSQVTQELRA | LMDETMKELK | AYKSELEEQL | ||||
| TPVAEETRAR | LSKELQAAQA | RLGADMEDVC | GRLVQYRGEV | QAMLGQSTEE | ||||
| LRVRLASHLR | KLRKRLLRDA | DDLQKRLAVY | QAGAREGAER | GLSAIRERLG | ||||
| PLVEQGRVRA | ATVGSLAGQP | LQERAQAWGE | RLRARMEEMG | SRTRDRLDEV | ||||
| KEQVAEVRAK | LEEQAQQIRL | QAEAFQARLK | SWFEPLVEDM | QRQWAGLVEK | ||||
| VQAAVGTSAA | PVPSDNH |
- Simboli
C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin
Polimorfizmi
urediAPOE je polimorfan,[19][20] s tri glavna alela (epsilon 2, epsilon 3 i epsilon 4): APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158) i APOE-ε4 (arg112, arg158).[5][21][22]
Iako se ovi alelni oblici međusobno razlikuju po samo jednoj ili dvije aminokiseline na položajima 112 i 158,[23][24][25] ove razlike mijenjaju strukturu i funkciju APOE-a.
| Polimorfizam | Svjetska učestalost alela | Značaj za bolest |
|---|---|---|
| ε2 (rs7412-T, rs429358-T) | 8,4%[9] | Ova varijanta apoproteina veže se slabo za receptore na ćelijskoj površini, dok se E3 i E4 dobro vežu.[26] E2 je povezan i sa povećanim i sa smanjenim rizikom od ateroskleroze. Osobe s kombinacijom E2 / E2 mogu polahko očistiti prehrambene masnoće i biti izloženi većem riziku od ranih vaskularnih bolesti i genetičkih poremećaja hiperlipoproteinemija tipa III – 94,4% oboljelih od takve bolesti su E2 / E2, ali samo ∼2% E2 / E2 je razvija, pa će vjerovatno biti uključeni i drugi okolišni i genetički faktori (poput holesterola u prehrani i starosti).[27][28][29] Smatra se da je E2 također uključen u Parkinsonovu bolest,[30] ali ovaj nalaz nije ponovljen u većoj studiji stanovništva.[31] |
| ε3 (rs7412-C, rs429358-T) | 77,9%[9] | Ova varijanta se smatra "neutralnim" genotipom APOE . |
| ε4 (rs7412-C, rs429358-C) | 13,7%[9] | E4 je upleten u aterosklerozu, Alzheimerova bolest,[32][33] oštećena kognitivne funkcije,[34][35] smanjen hipokampusni volumen,[35] HIV,[36] brže napredovanje bolesti multipla skleroza,[37][38] nepovoljan ishod nakon traumatske ozljede mozga,[39] ishemijska cerebrovaskularna bolest,[40] apneja u snu,[41][42] ubrzano skraćivanje telomera,[43] smanjeno izrastanje neurita,[44] i COVID-19.[45] Međutim, E4 je takođe povezan sa poboljšanim statusom za vitamin D i kalcij,[46] veća plodnost,[47] zaštita od infekcija i neuhranjenosti ranog djetinjstva[48] i smanjena smrtnost fetusa, perinatalna i novorođenčadi.[49] |
Od 2007. godine još je mnogo toga trebalo naučiti o izoformama APOE, uključujući interakciju drugih potencijalno zaštitnih genetičkih polimorfizama, pa se savjetuje oprez prije davanja odlučujućih izjava o utjecaju polimorfizama APOE na kogniciju i razvoj Alzheimerove bolesti. Od 2007. godine nije bilo dokaza da APOE polimorfizmi utiču na kogniciju u mlađim dobnim skupinama (osim moguće povećane epizodne sposobnosti pamćenja i neuronske efikasnosti u mlađim dobnim skupinama APOE4), niti da izoforma APOE4 dovodi pojedince u povećani rizik od bilo koje zarazne bolesti.[50]
Funkcija
urediAPOE transportuje lipide, rastvorljive u mastima vitamine i holesterol u limfni sistem, a zatim u krvotok. Sintetizira se uglavnom u jetri, ali je pronađen i u drugim tkivima kao što su mozak, bubreg i slezena.[21] U nervnom sistemu, tipovi neuronskih ćelija, posebno astroglija i mikroglija, su primarni proizvođači APOE, dok neuroni preferencijalno eksprimiraju receptore za APOE.[51] Postoji sedam identificiranih sisarskih receptora za APOE, koji pripadaju evolucijski konzerviranoj porodici LDLR.[52]
APOE je u početku prepoznat po važnosti u metabolizmu lipoproteina i kardiovaskularna bolest. Defekti u APOE rezultiraju porodičnom disbetalipoproteinemijom aka tip III hiperlipoproteinemija (HLP III), u kojima su povećani plazmatski holesterol i trigliceridi posljedica oštećenog klirensa hilomikrona, VLDL i LDL.[7][53] U novije vrijeme proučavan je zbog njegove uloge u nekoliko bioloških procesa koji nisu izravno povezani sa transportom lipoproteina, uključujući Alzheimerovu bolest (AD), imunoregulaciju i kogniciju.[54] Iako tačni mehanizmi tek trebaju biti razjašnjeni, izoforma 4 APOE, kodirana alelom APOE, povezana je s povećanim nivoima kalcijevih iona i apoptoza nakon mehaničkih povreda.[55]
Na polju imunske regulacije, sve veći broj studija ukazuje na interakciju APOE sa mnogim procesima, uključujući suzbijanje proliferacije T-ćelija, regulaciju funkcionisanja makrofaga, olakšavanje prezentacije lipidnog antigena (CD1)[56] do T-ćelija prirodnih ubicea, kao i modulacij upala i oksidacija.[57] APOE proizvode makrofagi, a pokazalo se da je sekrecija APOE ograničena na klasične monocite u PBMC, a sekrecija APOE monocitima dolje je regulirana upalnim citokinima, a pojačana putem TGF-beta.[58]
Klinički značaj
urediAlzheimerova bolest
urediOd 2012. godine, varijanta E4 bila je najveći poznati genetički faktor rizika za sporadični kasni nastup Alzheimerove bolesti (AD) u različitim etničkim skupinama.[59] However, the E4 variant does not correlate with risk in every population. Nigerian people have the highest observed frequency of the APOE4 allele in world populations,[60] but AD is rare among them.[60][61] This may be due to their low cholesterol levels.[60][61][62][63] Kavkazoidni i japanski nositelji dva alela E4 imaju između 10 i 30 puta veći rizik od razvoja AD do 75. godine života, u odnosu na one koji nemaju alele E4. To može biti uzrokovano interakcijom s amiloidom.[64] Alzheimerovu bolest karakteriziraju nakupine agregata peptidnih beta-amiloida. Apolipoprotein E pojačava proteolitsku razgradnju ovog peptida, kako unutar tako i između ćelija. Izoforma APOE-ε4 nije toliko učinkovita kao ostali u podsticanju ovih reakcija, što rezultira povećanom ranjivošću na AD kod osoba s tom genskom varijacijom.[65]
Iako 40–65% pacijenata sa AD ima barem jednu kopiju alela ε4, APOE4 nije determinanta bolesti. Najmanje jedna trećina pacijenata sa AD je negativna na APOE4, a neki homozigoti na APOE4 nikada ne razviju bolest. Ipak oni sa dva alela ε4 imaju i do 20 puta veći rizik od razvoja AD.[66] Također postoje dokazi da alel APOE2 može imati zaštitnu ulogu u AD.[67] Dakle, genotip koji je najugroženiji za Alzheimerovu bolest i u ranijoj dobi je APOE4,4. Koristeći genotip APOE3,3 kao referentnu vrijednost (s osobama za koje se ovaj genotip smatra rizikom od 1,0), osobe sa genotipom APOE4,4 imaju omjer šansi od 14,9 za razvoj Alzheimerove bolesti. Osobe s genotipom APOE 3,4 suočavaju se s omjerom šansi 3,2, a ljudi s kopijom 2 alela i 4 alela (APOE2,4) imaju omjer izgleda 2,6. Osobe s po jednom kopijom od 2 alela i 3 alela (APOE2,3) imaju omjer šansi 0,6. Osobe s dvije kopije alela 2 (APOE2,2) također imaju omjer šansi 0,6.[68]
| Procijenjena frekvencija (%) alela APOE u svjetskoj kavkazoidnoj populaciji[68] | ||||
| Alel | ε2 | ε3 | ε4 | |
|---|---|---|---|---|
| Opća frekvencija | 8,4 | 77,9 | 13,7 | |
| Frekvencija AD | 3,9 | 59,4 | 36,7 | |
Iako je utvrđeno da ApoE4 uveliko povećava izglede da će osoba razviti Alzheimerovu bolest, istraživanje iz 2002. godine zaključilo je da su osobe s bilo kojom kombinacijom alela APOE, visoki ukupni holesterol u serumu i povišeni krvni pritisak u srednjem vijeku života neovisni faktori rizika, koji zajedno mogu gotovo utrostručiti rizik da će kasnije razviti AD. Projektirajući na osnovu svojih podataka, neki istraživači sugeriraju da snižavanje nivoa holesterola u serumu može smanjiti rizik osobe za Alzheimerovu bolest, čak i ako ima dva alela ApoE4, smanjujući tako rizik od devet ili deset puta veće šanse za smanjenje AD na samo dva puta veće šanse.
U žena je vjerovatnije da će razviti AD od muškaraca u većini dobnih skupina i APOE genotipova. Premorbidne žene sa alelom ε4 imaju znatno više nervne disfunkcije od muškaraca.[69]
Ateroskleroza
urediNokaut-miševi kojima nedostaje gen apolipoprotein-E (APOE– /–) razvija ekstremnu hiperholesterolemiju, kada se hrani hranom sa puno masnoće.[70]
Malarija
urediNokaut-miševi APOE−/− pokazuju izrazito slabljenje cerebralne malarije i povećano preživljavanje, kao i smanjenu sekvestraciju parazita i T-ćelija u mozgu, vjerovatno zbog zaštite krvno-moždane barijere.[71] Studije na ljudima pokazale su da polimorfizam APOE2 korelira s ranijom infekcijom, a polimorfizmi APOE3 / 4 povećavaju vjerovatnoću teške malarije.[72]
Interakcije
urediMapa interaktivnog puta
urediReference
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Vanjski linkovi
uredi- Apolipoproteins E na US National Library of Medicine Medical Subject Headings (MeSH)
- apoe4.info – website for APOE-epsilon-4 carriers
- Lokacija ljudskog genoma APOE i stranica sa detaljima o genu APOE u UCSC Genome Browseru.
- P02649