Receptory mastných kyselin a endokanabinoidů; lipidové rafty

Receptory mastných kyselin a endokanabinoidů; lipidové rafty

Receptory mastnch kyselin a endokanabinoid; lipidov rafty [email protected] .cz Receptory mastnch kyselin 1) Peroxisomal proliferator-activated receptors (PPAR) jadern 2) Free-fatty acid-activated receptors (FFAR) na povrchu bunk, spaen s G-proteiny Receptory PPAR

3 isoformy: PPAR PPAR (nkdy nazvn i ) PPAR Reguluj metabolismus lipid: v se na responsivn elemen-ty a stimuluj trankripci gen oxidace i syntzy lipid

Na DNA se v ve form heterodimeru s retinoid X receptorem (RXR, aktivovn kyselinou 9-cis retinovou) (oxidovan LDL) (PPAR responsive element) Ligandy receptor PPAR Syntetick Prodn Hlavn pirozen ligandy: voln FA s dlouhm

etzcem (>12C), pedevm polynepolyne nasycen FA HODE=hydroxyoktadekadienov kys Role PPAR v lipidovm metabolismu PPAR reguluje expresi gen astncch se oxidace lipid (hlavn v srdci, jtrech, svalech) PPAR reguluje expresi gen zapojench do lipogeneze a diferenciace

adipocyt v bl tukov tkni PPAR Vysok exprese v tknch s intenzivn -oxidac: jtra, srdce, kostern sval, ledviny, hnd tuk Exprese se zvyuje bhem hladovn a stresu (tj. pi stimulaci uvolovn FA z tukov tkn) Funkce: regulace pjmu FA do bunk aktivace FA -oxidace FA stimuluje hlavn peroxisomln oxidaci, v men me i mitochondriln

Liva ze skupiny fibrt (bezafibrt) jsou innmi aktivtory PPAR a sniuj hladiny lipid Geny pod kontrolou PPAR LPL fatty acid transport protein (FATP), fatty acid translocase (FAT) acyl-CoA synthetasa

enzymy peroxisomln -oxidace (acyl-CoA oxidasa, thiolasa) enzymy mitochondriln -oxidace (CPT1, acyl-CoA dehydrogenasa) enzymy ketogeneze: ketogeneze 3-hydroxy-3-methylglutaryl-CoA synthasa PPAR/ Exprimovn v mnoha tknch, nejvce v mozku, tukov tkni, ki

Zvlt vysok exprese bhem vvoje (nap. v CNS) Pravdpodobn se astn diferenciace bunk CNS, myelinizace a lipidovho metabolismu v mozku astn se ale asi i zkladnch metabolickch funkc, nap. syntzy a obratu membrnovch lipid Podobn jako PPAR stimuluje expresi protein -oxidace (srdce) PPAR

3 isoformy: PPAR1 v mnoha tknch PPAR2 pedevm v tukov tkni PPAR3 jen v tukov tkni, makrofzch, stev Funkce: regulace diferenciace adipocyt anabolismus lipid: v tukov tkni reguluj expresi protein, kter se astn syntzy lipid: LPL, FATP Jsou aktivovny antidiabetiky ze skupiny thiazolidindion (glitazon, nap. rosiglitazon), kter zvyuj citlivost tkn k insulinu a sniuj hladiny FA a Glc Receptory FFAR

V plasmatick membrn (na rozdl od PPARs), spaen s G-proteiny Ligandem mohou bt i FA s krtkm etzcem, a to a do C1 (na rozdl od PPARs) 3 isoformy: FFA1R FFA2R FFA3R Psoben FFARs FFA1R

FFA2R FFA3R Expres pankreas, jtra, kostern sval, e srdce monocyty, tukov tk, neutrofily pankreas, buky imun. systmu Ligand stedn dlouh (od 10C) a y krtk FA (C1-C6)

podobn jako u FFA2R inky regulace regulace chemotax e kontrola produkce leptinu dlouh FA sekrece insulinu Endokanabinoidy Biologicky inn lipofiln ltky, kter aktivuj

kanabinoidov receptory Derivty arachidonov kys., produkovan po stimulaci z membr-novch fosfolipid Dva nejlpe popsan: Syntza anandamidu (PE) Reakce je iniciovna aktivac receptor neurotransmiter a/nebo zvenou intracelulrn

hladinou Ca2+ Syntza 2-arachidonoylglycerolu a) Opt pi koncentraci Ca2+ 2 drhy: fosfolipasa C + diacylglycerollipasa b) fosfolipasa A1 +

fosfolipasa C (specifick pro lyso-PI) Psoben Parakrinn jsou rychle odstraovny (pjem do bunk, hydrolza) Produkovny hlavn v: nervovm systmu imunitnm systmu Mnostv anandamidu v tknch je velmi nzk a navc v nkterch ppadech nepsob pln agonisticky jeho fyziologick vznam zstv nejasn

2-AG je naproti tomu agonistou CB1 i CB2 receptor a jeho mnostv v tknch je vy jsou tedy CB1 a CB2 pedevm receptory 2-AG? Kanabinoidov receptory Aktivovny THC (9-tetrahydrokanabinol) THC CB1: nejhojnj v CNS, dle v imunitnm systmu, plicch CB2: pedevm v imunitnm systmu (leukocyty, slezina, lymfatick uzliny) 7 transmembrnovch domn, spaen s Gi/Go proteiny

inhibice adenyltcyklasy inky 2-AG ze stimulovanch neuron potlauje uvolovn neuro-transmiter snenm intracelulrn koncentrace Ca2+ (?zklidnn excitovanch neuron jako prevence bunn smrti?) 2-AG potlauje dlouhodobou potenciaci ?Role v imunitn odpovdi organismu? (CB2 imunitn systm)

Stimulace CB1 inhibuje proliferaci bunk lidskho karcinomu prsu Lipidov rafty Plasmatick membrna: Nejde o zcela homogenn strukturu! Lipidov rafty (10-200 nm) Mikrodomny plasmatick membrny bohat na sfingolipidy a cholesterol, kter obsahuj etn signalizan a transportn proteiny

Odoln vi mrnm detergentm Vysoce dynamick a organizovan Vytvej prosted vhodn pro transport a konforman zmny signlnch molekul, ale i pro vstup patogen do hostitelsk buky (HIV, Ebola, cholera toxin) Model lipidovho raftu Vlcovit glycerofosfolipidy (GPLs) tvo neuspodanou fzi Lc membrny

Uspodan fze Lo raft: ve vnj vrstv cholesterol vypluje mezery mezi sfingolipidy (SM), ve vnitn uritmi (jehlanovitmi) GPLs Tato organizace zvyuje rigiditu membrny Proteiny v lipidovch raftech

Proteiny raft jsou asto ukotven pomoc GPI (glykosylfosfatidylinositol) Rafty obsahuj: receptory (Fas, MHCI, II) signln molekuly (Gproteiny, tyrosinkinasy) transportry (GLUT4, FAT) Lipidov rafty podporuj aktivaci T-lymfocyt TCR se pi aktivaci Tlymfocytu pesune do raft Vytvo se TCR-MHC komplexy a dojde k

agregaci kostimulanch molekul v raftech Fosforylace Tyr a zapojen signalizanch protein Kaveoly Druh raft, kter se vyznauje vysokm obsahem kaveolin (kaveolin-1,-2,-3) Kaveolin-1, integrln membrnov protein, tvo oligomery, kter se spojuj a vytvej v membrn prohlube

Mon role: signalizace transport vstup patogenu (SV40, E. Coli) Model vstupu HIV do buky pomoc raft V raftu se vytv komplex gp120 viru, CD4 a sfingolipid (SLs); SLs stabilizuj HIV na povrchu buky Raft se pohybuje ke koreceptoru pro komplex CD4gp120

SLs usnaduj konforman zmny gp120, kter vedou k odhalen N-konce gp41 viru (pvodn zanoen do kapsy tvoen gp120) Tento fzn peptid penetruje do plasmatick membrny hostitelsk buky Rafty v prionov infekci Interakce PrPC s lipidovmi rafty (sfingolipidy) asi stabilizuje normln konformaci PrPC

Tyto interakce lipidPrPC by mohly bt destabilizovny vnoenm exogennho PrPSc (uvolnnho z infikovan buky) do blzkosti PrPC Tvorba komplexu PrPC/PrPSc/koreceptor (asi spojenm raft) Konverze PrPC na PrPSc Propagace na povrchu buky

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