Grelin
Grelin ili lenomorelin, INN, je cirkulirajući hormon kojeg proizvode enteroendokrine ćelije gastrointestinalnog trakta, posebno želudac,[5][6] a često se naziva "hormonom gladi" jer povećava unos hrane.[6] Razina grelina u krvi je najviša prije obroka kada je osoba gladna, a na niži nivo vraća se nakon obroka.[6][7] Grelin također može pomoći i u pripremi za unos hrane,[6][8] povećanjem želučanog motiliteta i lučenja želučane kiseline.[6]
Grelin aktivira ćelije u prednjem režnju hipofize i hipotalamusno lučno jezgro,[6][9] uključujući neurone neuropeptida Y koji podstiču apetit.[6][10] Grelin stimulira moždane strukture koje imaju receptor – sekretagog receptor 1A (GHSR - 1A) hormona rasta.[6][11] Također učestvuje u regulaciji spoznaja nagrade,[12] učenja i pamćenja i tciklusa spavanje-buđenje, osjećanja okusa, ponašanje nagrađivanja i metabolizam glukoze.[6][13][14]
Historija i ime
urediGrelin je otkriven nakon što je receptor za grelin (nazvan receptor za sekretagog hormona rasta tipa 1A ili GHS-R) određen 1999.[6] Naziv hormona zasnovan je na njegovoj ulozi: growth hormone -releasing peptid, s pozivom na korijen protoindoevropska rekonstrukcija/ gʰreh₁-| gʰre– , što znači rasti.[6]
Gen, transkripcijjski proizvod i struktura
uredi
Gen GHRL proizvodi iRNK sa četiri egzona. Translacijom i preradom, nastaje pet proizvoda: prvi je "preprogrelin" sa 117 aminokiselina. (Homologan je promotilinu; oba su članovi porodice motilina. Cijepa se da bi se dobGhrelina.jpgio progrelin, koji se također cijepa da bi se dobio 28-aminokiselinski (necilirani) grelin i C-grelin. Pretpostavlja se da je obestatin odcijepljen od C-grelina.[15]
Grelin postaje aktivan samo kada je kaprilna kiselina kaprilna (oktanska) kiselina posttranslacijski povezan sa serinom enzima grelin O-aciltransferaza (GOAT), u 3-položaju. Nalazi se na ćelijskoj membrani grelinskih ćelija u želucu i pankreasu.[16] Neoktanoilirani oblik je dezacil grelin. Ne aktivira GHS-R receptor, ali ima druge efekte: srčani,[17] antigrelin,[18] appetite stimulation,[19] i inhibicija izlaska glukoze iz jetre.[20] Također su uočeni bočni lanci koji nisu oktanoil: i oni mogu pokrenuti receptor za grelin.[21] Konkretno, utvrđeno je da dekanoil grelin čini značajan dio grelina u opticaju kod miševa, ali od 2011. njegovo prisustvo kod ljudi nije utvrđeno.[22]
Grelinske ćelije
urediAlternativni nazivi
urediGrelinska ćelija je poznata i kao A-likolika ćelija (gušterača), X-ćelija (zbog nepoznate funkcije), X / A-likolika ćelija (pacovi), epsilon ćelija (gušterača), P/D sub 1 ćelija (ljudi) i Gr ćelija (skraćenica od grelinska ćelija).[23]
Lokacija
urediGrelin ćelije nalaze se uglavnom u želucu [24] i dvanaestpalačnom crijevu, ali također i u jejunumu, plućima i gušteračinim otočićima,[25] gonadama, kori nadbubrežne žlijezde, placenti i bubrezima. Također se pokazalo da se mjestimično luči i u mozgu.[26]
Obilježja
urediGrelinske ćelije se nalaze u oksintskim žlijezdama (20% ćelija),[27] piloričnim žlijezdama i tankom crijevu. To su jajolike ćelije sa zrncima (granulama).[28] They have gastrin receptors.[29] Neke proizvode nesfatin-1.[30] Grelinske ćelije se na kraju diferenciraju u gušterači: one su progenitorne ćelije koje tamo mogu stvoriti A-ćelije, PP ćelije i Beta-ćelije.[31]
Funkcija i mehanizam djelovanja
urediGrelin je sudionik u regulaciji složenog procesa energetske homeostaze koji prilagođava i unos energije – podešavanjem signala gladi – i izlaz energije, podešavanjem udjela energije koja ide u proizvodnju ATP , skladištenje masti, glikogena i kratkoročni gubitak toplote. Neto rezultat ovih procesa ogleda se u tjelesnoj težini i pod stalnim je nadzorom i prilagođavanjem, na osnovu metaboličkih signala i potreba. U bilo kojem trenutku, može biti u ravnoteži ili neravnoteži. Komunikacija želudac – mozak, važan je dio energetske homeostaze i vjerovatno je nekoliko komunikacijskih putova, uključujući želučani unutarćelijski put S6K1 posredovanja interakcije grelina, nesfatina i endokannabinoida želučanid sistema [32] i uzlaznih (aferentnih) i silaznih (eferentnih) vagusnih sigmala.
Grelini i njihve sintetske zamjene (sekretagog hormona rasta povećavaju tjelesnu težinu i masnu masu[33][34][35] ciljajući receptore u the lučnom jezgru[9] koji uključuju neuronski neuropeptid Y (NPY) i agouti-srodni protein (AgRP).[10][36] Ovi neuroni reagirauju na grelin i osetljivi su i na leptin i na insulin.[37] Grelin smanjuje osjetljivost želučanih vagus nih uzlaznih nervnih vlakana, tako da su manje osjetljiva na rastezanje želuca.[38]
Pored svoje funkcije u energetskoj homeostazi, grelin također aktivira holinergijsko-dopaminergijsku nagradnu vezu u ulazima u ventralno tegmentno područje i u mezolimbni put ,[39] krug koji komunicira hedonske i ojačavajuće aspekte prirodnih nagrada,[13] such as food and addictive drugs such as ethanol.[37][40][41] Grelinski receptori nalaze se u neuronima tog kruga.[12][13] Za osjećaj nagrade od alkohola, potrebna je signalizacija hipotalamusnog grelina[42] i ukusna / korisna hrana.[43][44]
Grelin je povezan s izazivanjem apetita i ponašanjem u prehrani. Razina grelina u cirkulaciji je najviša neposredno prije obroka, a najniža neposredno nakon objedovanja.[45][46] Pokazalo se da injekcije grelina kod ljudi i pacova povećavaju unos hrane na način koji ovisi o dozi.[47] Dakle, što se više ubrizga grelina, to se više konzumira. Međutim, grelin ne povećava veličinu obroka, već samo njihov broj.[48] Injekcije grelina također povećavaju motivaciju životinje da traži hranu, ponašanja koja uključuju pojačano njuškanje, traženje hrane i gomilanje hrane. Tjelesna težina regulira se energetskom ravnotežom, količinom energije koja se uzima u odnosu na količinu energije koja se troši tokom dužeg vremenskog perioda. Studije su pokazale da su nivoi grelina u negativnoj korelaciji sa težinom. Ovi podaci sugeriraju da grelin funkcionira kao signal gojaznosti, glasnik između tjelesnih zaliha energije i mozga.[8]
Razine u krvi
urediNivoi u krvi su u opsegu pmol/l. Mogu se izmjeriti i aktivni i ukupni grelin.[49] Koncentracije grelina u cirkulaciji rastu prije jela i padaju nakon toga,[45] snažnije kao odgovor na proteine i ugljikohidrate nego na lipide..[22]
Grelinski receptor
urediGrelinov receptor GHS-R1a (spojnica-varijanta receptor sekretagoga hormona rasta, pri čemu je spoj GHS-R1b neaktivan) uključen je u posredovanje bioloških efekata grelina širokog spektra, uključujući: stimulaciju oslobađanja hormona rasta, povećanje gladi, modulaciju metabolizma glukoze i lipida, regulaciju gastrointestinalnog motiliteta i sekrecije, zaštitu neuronskih i kardiovaskularnih ćelija i regulaciju imunske funkcije.[50] Prisutni su u velikoj gustoći u hipotalamusu i hipofizi, na vagusnom nervu (i na tijelima aferentnih ćelija i na eferentnim nervnim završecima) i u čitavom gastrointestinalnom traktu.[16][38]
Mjesto aktivnosti
urediMetabolizam glukoze
urediČitav grelinski sistem (dAG, AG, GHS-R i GOAT) ima gluko-regulatorno djelovanje.[51]
Spavanje
urediPreliminarna istraživanja pokazuju da grelin sudjeluje u regulaciji cirkadijskih ritmova. Pregled je izvijestio da nije pronađen čvrst dokaz da je ograničenje sna uticalo na nivo grelina ili leptina ili na potrošnju energije.[52]
Reproductivni sistem
urediGrelin djeluje inhibitorno na sekreciju gonadotropin-oslobađajućeg hormona (GnRH). Može prouzrokovati smanjenu plodnost.[53]
Fetus i novorođenče
urediGrelin rano proizvode fetusna pluća i pospješuje njihov rast.[54] Razine grelina u krvi pupčane vrpce pokazuju korelaciju između nivoa grelina i porođajne težine.[49]
Anoreksija i gojaznost
urediKoncentracija grelina u plazmi gojaznih osoba niža je od one kod mršavijih osoba,[6][55] sugerirajući da grelin ne doprinosi pretilosti, osim u slučajevima Prader-Willijevim sindromom inducirane gojaznosti, gdje su visoke razine grelina u korelaciji s povećanim unosom hrane.[56][57] Osobe sa poremećsjrm zvanim anorexia nervosa imaju visok nivo grelina u plazmi[58] u poređenju sa vitkom i normalnom konstitucijom, kao kontrolom.[59][60] Razina grelina raste u doba dana od ponoći do zore kod mršavijih ljudi, što sugerira da postoji mahana u cirkadijskom ritmu gojaznih osoba.[61] Ghrelin levels are high in people with cancer-induced cachexia.[62] Nema dovoljno dokaza da bi se zaključilo bilo za ili protiv upotrebe grelina u liječenju kaheksije povezane s kancerom.[63]
Upravljanje bolestima
urediOperacija želučane premosnice
urediOperacija gastrične premosnice ne samo da smanjuje kapacitet crijeva za hranu, već i razinu grelina u usporedbi s mršavim ljudima i onima koji su mršavili dijetom.[6][64] Studije nisu razjasnile da li se razina grelina vraća u normalu kod ljudi koji su imali operaciju želučane premosnice nakon stabiliziranja gubitka kilograma.[65] Operacija gastričnog bajpasa, koja uključuje gastrektomija vertikalnih rukavaca, dugoročno smanjuje nivo grelina u plazmi za oko 60%.[66]
Također pogledajte
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