Tšusumetso ea 'γ-oryzanol e khethehileng ea raese e nang le li-epigenetic ho feto-fetoha ha dopamine D2 receptors boemong ba boko ba boko bo botenya bo bakoang ke mafura a mangata (2017)

. 2017; 60 (8): 1502-1511.

E hatisitsoe Inthaneteng 2017 May 20. doi:  10.1007/s00125-017-4305-4

PMCID: PMC5491592

inahaneloang

Merero / khopolo-taba

Ho ja lijo tse ngata ho tlisa matla ho batho le litoeba. Liphuputso tsa morao-rao ho batho le litoeba li bontšitse hore ho lemalla mafura ho na le mokhoa o tloaelehileng oa ho lemalla joala, nicotine le lithethefatsi ka lebaka la ho se sebetse ha mekhoa ea boipheliso ea boko. Ho 'nile ha totobatsoa hore lijo tse nang le mafura a mangata (HFD) li thibela pontšo ea dopamine D2 receptor (D2R) ho striatum, molaoli oa bohlokoa oa tsamaiso ea boko ba boko, e hlahisang ho ja lijo tse ngata haholo. Re kile ra tlaleha hore γ-oryzanol e entsoeng ka raese e hlahisitsoeng ke raese e ne e khetholla khetho ea HFD ka tsela e ts'oanang ea ho laola. Ka lebaka lena re ile ra hlahloba monyetla oa hore γ-oryzanol e tla fetola mokhoa oa ho sebetsa ha boko boemong ba litoeba.

mekhoa

Monna C57BL / 6J litoeba tsa fepa HFD li ne li tšoaroa ka molomo le γ-oryzanol, 'me limolek'hule tse ntseng li e-ba teng liphatseng tsa D2R li ile tsa hlahlojoa. Tšusumetso ea γ-oryzanol ka methylation ea DNA ea mothetsi oa D2R le liphetoho tse latelang likhethong tsa mafura a lijo li ile tsa hlahlojoa. Ho phaella moo, liphello tsa 5-aza-2'-deoxycytidine, inhibitor e matla ea DNA methyltransferases (DNMTs), ka lijo tsa lijo, pontšo ea D2R le litekanyetso tsa DNMTs ho striatum li ile tsa batlisisoa. Liphello tse sa thibeleng tsa γ-oryzanol mosebetsing oa DNMTs li ne li hlahlojoa ka mochine ka in vitro.

Results

Ka striatum ho tloha litoeba tse fetileng HFD, tlhahiso ea D2R e fokotsehile ka ho eketseha ha methylation ea DNA ea sebaka se khothalletsang D2R. Ho tsamaisoa ka molomo oa γ-oryzanol ho fokolitse polelo le ts'ebetsong ea DNMTs, ka tsela eo ho tsosolosa boemo ba D2R ho striatum. Ho thibela tšoaetso ea mafu a DNMTs ka 5-aza-2'-deoxycytidine hape e ntlafalitse khetho ea mafura a lijo. Tumellanong le liphuputso tsena, liteko tsa enzymatic in vitro li bontšitse hore γ-oryzanol e thibela mosebetsi oa DNMTs.

Sephetho / tlhaloso

Re bontsitse hore γ-oryzanol e ntlafatsa DNA hypermethylation ea DFN e entsoeng ke HFD sebakeng se ts'ebetso ea D2R ka statum ea litoeba. Paledigm ea rona ea liteko e totobatsa γ-oryzanol e le ntho e tšepisang ea ho loantša bolutu le thepa e ikhethang ea ho ba modulator ea libuka.

Lisebelisoa tsa elektronike tse tlatsetsang

Phetolelo ea inthanete ea sehlooho sena (etsa: 10.1007 / s00125-017-4305-4) e na le boitsebiso bo hlophisitsoeng ka lithaka empa bo sa sebelisoe, bo fumanehang ho basebelisi ba nang le matla.

Keywords: DNA methylation, Dopamine, Epigenetics, Ho fepa boitšoaro, phepo e nepahetseng, botenya, moputso, striatum, mofuta oa 2 lefu la tsoekere

Selelekela

Ho ja haholo batho ba nang le bo-mpoli ba arolelana, bonyane karolo e 'ngoe, mekhoa e tloaelehileng ea ho lema joala, nicotine le lithethefatsi []. Hape hammoho le taolo ea pheko ea hormone le ea hormonal ea takatso ea lijo, boko bo fumanoang tsamaisong, haholo-holo bo-dopamine receptor pontšo, bo amana haufi-ufi le mokhoa oa ho fepa kapa oa hedonic []. Phuputso e fetileng ho likhoto e bontšitse hore ho kokota ha mochine oa dopamine D2 receptor (D2R) ka lentivirus-mediated short hairpin e sitisa RNA ho senya ka ho lemalla ho lemalla ho lemalla le ho batla lijo joaloka ho batla []. Ka lebaka la tekanyo e fokolang ea D2R, storum ea matšoafo ha e amohele melemo ea lijo ha e bapisoa le lihlopha tse laolehileng tse laolang batho ba bangata le litoeba [-]. Ho ea ka khopolo ena, ea TaqKe ile ka khaotsa ho etsa joalo ANKK1 sebaka sa liphatsa tsa lefutso (encoding domain DRD2 / ankyrin e pheta-pheta le kinase e nang le 1), e fokotsang tlhahiso ea pele ea D2R, e amana le phantotype e feteletseng ho batho [], ha liphello tsa ho lahleheloa ke boima ka mor'a ho buuoa ka bariatric li amahanngoa le boholo ba D2R bo hlaselang []. Litlaleho tsena li fana ka maikutlo a bohlokoa ba bohlokoa ba ho hlasela D2R e le phetolelo ea morao-rao ea phekolo ea botenya. Leha ho le joalo, lithethefatsi tse ling tse entsoeng tse ileng tsa etsoa bokong ea boko li ile tsa baka liphello tse bohloko tse ngata, tse akarelletsang mathata a tebileng a kelello, e leng se ileng sa etsa hore qetellong ba tlohe litleliniking [].

Liphetoho tsa Epigenetic ha li bohlokoa feela bakeng sa nts'etsopele le phapang, empa hape hobane li hlaha ka lebaka la liphetoho tsa tikoloho, ho kenyeletsa le ho ja le mokhoa oa bophelo []. DNA methylation ke ketsahalo e khōlō ea epigenetic bakeng sa botsitso ba liphatsa tsa lefutso []. Likokoanyana, ho pepa ha motsoako oa lihlahisoa tse ngata tsa mafura (HFD) ho fetola metsoako ea DNA methylation ka hare ho bohareng ba moputso oa bana, e leng se lebisang ho ho feta ha HFD ke li-pups []. Ka ho khetheha, DNA methyltransferases (DNMTs) e phetha karolo ea bohlokoa ho laola mokhoa oa bobeli oa phepo le liketsahalo tsa 'mele [, ], ho fana ka maikutlo a hore DNMTs e ka ba tšepiso ea liphekolo tsa phekolo ea botenya ba lefu la tsoekere-lefu la tsoekere. Habohlokoa, lisebelisoa tse ling tsa tlhaho tse tsoang lijo, tse kenyeletsang acid e caffeic le epigallocatechin, li tsejoa hore li sebetsa joaloka DNMT inhibitors [, ].

Re sa tsoa bonts'a hore motsoako o khethehileng oa raese γ-oryzanol, motsoako oa acid e entsoeng ka ferone le li-phytosterol tse 'maloa, o thibela khethollo ea mafura a lijo ka ho fokotseha ha khatello ea maikutlo ea hypothalamic endoplasmic reticulum (ER) []. Ho litoeba le mebutlanyana, e-oryzanol e tsamaisoang ka molomo e ne e kenngoa ka potlako ho tloha mala 'me e ajoa haholo-holo ho boko [, ]. Ho nka liphuputso tsena hammoho, lihlahisoa tse hlahisoang ke lijo tsa tlhaho tse sebetsang tsamaisong ea methapo ea mantlha e ka ba mokhoa o mong oa ho ntlafatsa boitšoaro bo bobe ba ho fepa ka botenya. Ka moelelo ona, re ile ra leka khopolo ea hore γ-oryzanol e ne e tla fetola boemo ba DNA ea methylation boemong ba moputso oa boko, e leng se etsang hore ho be le tlhokomelo ea khetho ea HFD ho litoeba.

mekhoa

Animals

Litoeba tse lilemo li supileng tsa C57BL / 6J tse fumanoang ho Charles River Laboratories Japan (Kanagawa, Japane) li ile tsa lula (3-4 ka hoko) maemong a se nang likokoana-hloko ho 24 ° C tlasa leseli la 12 h / 12 h / lefifi potoloho. Kamora beke ea tloaelo, litoeba tsa libeke tse 8 li ne li lekana 'me li arotsoe ka lihlopha tse peli kapa tse tharo ho ea tekong e ngoe le e ngoe. Litoeba li ne li lumelloa ho fumana lijo le metsi mahala. Liteko tsohle tsa liphoofolo li amohetsoe ke Komiti ea Boitšoaro ba Boiteko ba Liphoofolo ea Univesithi ea Ryukyus (Nom. 5352, 5718 le 5943).

Tsamaiso ea γ-oryzanol le 5-aza-2'-deoxycytidine

E le ho hlahloba khetho ea HFD, γ-oryzanol (Wako Pure Chemical Industries, Osaka, Japane) e ne e laoloa ho litoeba tsa libeke tsa 8 ka gavage nakong ea teko ea khetho ea lijo joalokaha ho hlalositsoe pele [, ]. Bakeng sa liteko tse ling, HFD (D12079B; Mefuta ea Lipatlisiso, New Brunswick, NJ, USA) e nang le 0.4% γ-oryzanol e entsoe e le pellets. Likarolo tse ling tsa lijo li bontšoa tafoleng ea elektronike ea tlatsetso (ESM) 1. Kamora libeke tse 12 tsa ho fepa, lisele li ile tsa bokelloa ho tsoa ho striatum le hypothalamus. Ho ja γ-oryzanol letsatsi le leng le le leng, ho hakanngoa ho tsoa ho lijo tse bolelang lijo tsa litoeba, e ne e ka ba boima ba 'mele ba 320 μg / g. Tekanyo ea γ-oryzanol e ne e reriloe joalo ka ha ho hlalositsoe pejana []. 5-aza-2'-deoxycytidine (5-aza-dC; Sigma-Aldrich, St Louis, MO, USA) e ile ea entoa ka hare ho 'mele (0.25 μg / g boima ba' mele) makhetlo a mararo ka beke bakeng sa libeke tse 12 [].

Tekanyo ea khetho ea mafura a lijo

Ho hlahloba lithahasello tsa mafura a lijo, liteko tsa lijo li ne li fana ka khetho pakeng tsa chow le HFD (D12450B le D12451; Lijo tsa Lipatlisiso) joalokaha ho hlalositsoe pele []. Likarolo tsa lijo li bontšoa tafoleng ea ESM 1. Ka bokhutšoanyane, litoeba li ne li lumelloa ho fumana mahala ho chow le HFD. Ho kenella ha chow le HFD ho ne ho lekanyetsoa beke le beke mme ho hlahlojoa liphetoho bakeng sa mafura a phepo. Khetho ea HFD e baliloe ho ea ka foromo: HFD preference = [(Ho noa HFD / kakaretso ea lijo) × 100].

Bisulphite e arohanang DNA methylation

DNA e ile ea hloekisoa ho sebelisoa DNeasy Blood & Tissue Kit (QIAGEN, Tokyo, Japane). Tharollo ea DNA e ne e tsoakane le 3 mol / l NaOH e sa tsoa lokisoa, e koahetsoeng ka 37 ° C bakeng sa 15 min mme e ekelitsoe ho 5.3 mol / l urea, 1.7 mol / l sodium bisulphite le 4.9 mmol / l hydroquinone. Tharollo e ile ea fuoa lipotoloho tse 15 tsa denaturation ho 95 ° C bakeng sa 30 s le ho kenella ho 50 ° C bakeng sa 15 min []. DNA e entsoeng ka bisulphite e ile ea hloekisoa ka ho sebelisa Setsi sa Ho Hloekisa PCR (QEAGEN) le ho ntlafatsoa ke PCR e sebelisa KAPA HiFi HotStart Uracil + ReadyMix PCR Kit (KAPA Biosystems, Woburn, MA, USA) le mathoasong a sebaka sa CpG sa sebaka se khothalletsang D2R . Liphetho tsa ho qala ho ne ho e-na le tse latelang: pele ho pele, 5'-GTAAGAATTGGTTGGTTGGAGTTAAAA-3 '; reverse primer, 5'-ACCCTACCCTCTAAAACCACAACTAC-3 '. Ka mor'a moo, li-adapter li ile tsa kenngoa 'me tsa hloekisoa ho sebelisa Agencourt AMPure XP (Beckman Coulter, Brea, CA, USA). Likarolo li ile tsa kopanngoa 'me tsa kenngoa ho GS Junior (Roche Diagnostics, Tokyo, Japane) bakeng sa ho etsa sekhetho ho ea ka protocol ea moetsi. Tekanyo ea methylation e ne e hlahisoa e le karolo ea methylated cytosines lihlahisoa tsohle tsa cytosine.

Tlhahlobo ea mesebetsi ea DNMT

Tlhahlobo ea mesebetsi ea DNMT e entsoeng ka matla a phekolo e ile ea etsoa ho sebelisa EpiQuik DNA Methyltransferase Action / Inhibition Assay Kit (Epigentek Group, Brooklyn, NY, USA) le EPIgeneous Methyltransferase Assay kit (Cisbio Japane, Chiba, Japane) ho latela melao ea moetsi.

Ho hlahloba tšebetso ea ho thibela tšebetso ea motsoako ka mong ka methylation ea DNA, ho thehoa ha S-adenosyl-l-homocysteine ​​(SAH) e ne e lekantsoe boteng ba komporo e ngoe le e ngoe (20 μmol / l bakeng sa liteko tsa ho lekola), S-adenosyl methionine (SAM; 10 μmol / l) le substrate ea DNMT (4 ng / μl) ho 37 ° C bakeng sa 90 min. Ho lekola Michaelis-Menten kinetics, DNMT1 (20 μmol / l) e kopantsoe le γ-oryzanol, SAM (5 μmol / l) le mohopolo o bontšitsoeng oa poly dI-dC ho 37 ° C bakeng sa 90 min. DNMT3a (100 μmol / l) le DNMT3b (100 μmol / l) li kopantsoe le γ-oryzanol, SAM (5 μmol / l) le mohopolo o bontšitsoeng oa poly dG · dC ho 37 ° C bakeng sa 120 min. Liteko li ne li etsoa ka makhetlo a mane. Protheine e ntšitsoeng (0.75 mg / ml) e kopantsoe le SAM (5 μmol / l), poly dI-dC (5 μg / ml), le poly dG · dC (5 μg / ml) ho 40 ° C bakeng sa 120 min, le Sebopeho sa SAH se ne se lekantsoe.

Mesebetsi e amohelehang ea li-receptor-γ ea Estrogen

Ts'ebetso e khahlano ea γ-oryzanol ho receptor-γ (ERRγ) e amanang le estrogen e ile ea hlahlojoa ho sebelisoa Sisteme ea Receptor Gamma Reporter Assay System ea Human Estrogen (INDIGO Bioscience, State College, PA, USA) ho latela protocol ea moetsi. Ka bokhutšoanyane, lisele tsa baqolotsi ba litaba tsa mammalian bao e seng batho ba hlalosang ERRγ e sebetsang li ile tsa pepesetsoa likhahla tse bontšitsoeng tsa komporo ka 'ngoe bakeng sa 24 h ka makhetlo a mararo.

Bophahamo ba Bophirimela

Sena se ile sa etsoa joalokaha ho hlalositsoe pele [] e nang le lithibela-mafu khahlanong le D2R (1: 500, mmutla), mopalami oa dopamine (DAT; 1: 500, mmutla), tyrosine hydroxylase (TH; 1: 1000, mmutla) (AB5084P, AB1591P le AB152, Merck Millipore, Billerica, MA, USA), transducer ea pontšo le activator ea transcript 3cy (STAT3α; 1: 1000, mmutla), DNMT1 (1: 1000, mmutla), DNMT3a (1: 1000, mmutla) (linomoro 8768, 5032 le 3598; Theknoloji ea ho saena sele, Tokyo, Japane), DNMT3b (1 μg / ml, mmutla), ERRγ (1: 1000, mmutla) le β-actin (1: 10,000, toeba) (ab16049, ab128930 le ab6276; Abcam, Cambridge, MA, USA).

Ntho e lekanang ea nako ea sebele ea PCR

Puo ea Gene e ne e hlahlojoa joalokaha e hlalositsoe pele []. MRNA maemo a ne a tloaelehile Rn18s (18S rRNA). The primer e behiloeng bakeng sa litekanyo tsa nako ea sebele ea PCR e akaretsitsoe ka lethathamong la ESM 2.

Tlhahlobo ea statistical

Lintlha li hlahisoa e le tse mpe ± SEM. ANOVA ea tsela e le 'ngoe le mehato e phetoang ANOVA e lateloang ke liteko tse ngata tsa papiso (mokhoa oa Bonferroni – Dunn) li sebelisitsoe moo ho hlokahalang. Seithuti t teko e ne e sebelisetsoa ho hlahloba phapang lipakeng tsa lihlopha tse peli Ho fapana ho ne ho nkoa ho le bohlokoa ho p <0.05.

Results

Ho thibela tšoaetso ea mafu a DNMTs ka 5-iza-dC ho fokolisa khetho ea mafura a lijo tsa mantlha

Ha litoeba li fepa HFD, DNA methylation sebakeng sa promoter D2R ka striatum e ne e eketseha haholo ha e bapisoa le litoeba tse fepa lijo tsa chow (feiga. (Fig.1a) .1a). Ka lehlakoreng le leng, hypothalamic DNA methylation sebakeng se tsosolosang sa D2R se ne se bonahala se le seholo ho feta sa statum tlas'a lijo tsa chow (p <0.01) (sa feiga. (Fig.1a, 1a, f) 'me ha ea fetoloa ke HFD (feiga. (Fig.1f) .1f). Ha litoeba li fepa HFD, DNA ea methylation e ntseng e eketseha sebakeng se ts'ebetso ea D2R ka statum e ne e tloaelehile ka ho phekoloa ka 5-aza-dC, e matla DNMT inhibitor (Fig. (Fig.1a) .1a). Ka lehlakoreng le leng, DNA methylation sebakeng se ts'ebetso ea D2R ho hypothalamus ha ea fetoha haholo ka phekolo le 5-aza-dC (sa fe. (Fig.1f) .1f). Ho striatum ea litoeba tse tona tse nang le libeke tse 20 li fepa HFD bakeng sa libeke tse 12, mRNA le li-protein tsa D2R li fokotsehile haholo (Fig. (Fig.1b, 1b, k, l). Ka lehlakoreng le leng, litekanyetso tsa dopamine D1 receptors (D1Rs, tse kentsoeng ke Drd1), e sebetsang ka tsela e fapaneng le D2Rs ka adenylyl cyclase le pontšo ea intracellular e kopanetsoeng, e sa fetohe (setšoantšo sa feiga. (Fig.1c) .1c). Ho feta moo, ho ne ho se na phetoho maemong a limolek'hule tse ling tse amanang le pontšo ea D2R, e kang TH le DAT mRNA le / kapa liprotheine (Fig. (Fig.1d, 1d, e, k, m). Ka lehlakoreng le leng, ha ho liphetoho tse bonahalang tse ileng tsa hlokomeloa ho hypothalamus, ho kenyeletsa le D2R (sa feiga. (Fig.1g-m) .1g-m). Ka ho hlakileng, li-protein tse ngata tsa D2R le TH ka hypothalamus li ne li le tlaase haholo ho feta tsa statum (sa feiga. (Fig.1l, 1l, m), mohlomong ho bonahatsa bohlokoa ba bohlokoa ba ho amohela dopamine receptor boemong ba moputso oa boko bo bapisoa le hypothalamus.

Feie. 1 

Ho thibela DNMTs ka 5-aza-dC ho thibela khetho ea HFD ka ho eketseha ha li-D2R ho statum ea litoeba tse fepehileng HFD. DNA methylation maemong a ts'ebetsong sebakeng sa D2R ka striatum (n = 3) (a) le hypothalamus (n = 3) ...

E le ho hlahloba hore na methylation ea DNA sebakeng se ts'ebetso ea D2R e ne e tla fetola khetho ea mafura a lijo, mokhoa oa ho fepa oa litoeba tsa 5-aza-dC-o ile oa hlahlojoa. Joalokaha ho lebeletsoe, 5-aza-dC e eketsa haholo mRNA le liprotheine tse ling tsa D2R ha ho etsoa litoeba tsa HFD (Fig. (Fig.1b, 1b, k, l). Ka lehlakoreng le leng, ho ne ho se na phello maemong a Drd1, Th 'me Slc6a3 (encoding DAT) ho striatum, kapa maemong a Drd2, Drd1, Th 'me Slc6a3 ho hypothalamus (sa feiga. (Fig.1c-e, 1c-e, g-m). Le hoja litoeba tse tšoaroang ka koloi li khethile HFD, khetho ea HFD e ne e fokotseha haholo ho litoeba tse tšoaroang ka 5-aza-dC (88% ea litekanyetso tsa litoeba tse tšoaroang ka koloi) (Setšoantšo sa Fig. (Fig.1n) .1n). Ka lebaka leo, phekolo le 5-aza-dC e fokotsa phaello ea boima ba 'mele (sa feiga. (Fig.11o).

γ-oryzanol e fokotsa likarolo tsa DNMTs ka mokhoa oa striatum oa litoeba tse feptjoang ke HFD

Joalokaha re kile ra tlaleha [], ho tsamaisoa ka molomo oa γ-oryzanol ho litoeba tsa banna ka gavage ho thibela haholo tlhahiso ea HFD (93% ea litekanyetso tsa litoeba tse tšoaroang ka koloi) (Setšoantšo sa Fig. (Fig.2a), 2a), ho fella ka ho hlokomoloha boima ba 'mele (Fig. (Fig.2b) .2b). Ka hona re ile ra hlahloba tšusumetso e ka bang le phello ea γ-oryzanol ka ho feto-fetoha ha epigenetic ea D2Rs ka striatum.

Feie. 2 

Tšusumetso e thibelang e-yyyzanol ho DNMTs ho litoeba tse fepang HFD. Khetho ea HFD (a) le boima ba 'mele (b) litoeba tse tšoaroang ke γ-oryzanol nakong ea likhetho tsa lijo tsa chow vs HFD (n = Lihopo tse 4; litoeba tse tharo ka lesakeng). Methati ea mRNA ea ...

Linthong tse phefolang, ho na le DNMTs tse tharo tse kholo-DNMT1, 3a le 3b. DNMT1 e sebetsa ho boloka methylation ea DNA, ha DNMT3a le 3b li phetha karolo ea ho ntlafatsa de novo DNA methylation []. E le hore re hlahlobe tšusumetso e ka bakoang ke γ-oryzanol ho DNMTs ka vivo, re hlahlobile litekanyetso tsa DNMTs boemong ba litoeba tse fepehileng ka HFD. Le hoja HFD ka ho se e ne e se na phello mRNA le li-protein tse ling tsa DNMTs ho sa tsotellehe striatum kapa hypothalamus, tlatsetso le γ-oryzanol e fokotseha haholo likarolo tsa DNMTs ho striatum empa eseng hypothalamus (Fig. (Fig.2c-e, 2c-e, g-i, k-n). Lintlha tsena li phahamisa monyetla oa hore γ-oryzanol e ka laola maemo a DNMTs ka mokhoa o itseng oa striatum. Ka mokhoa o ts'oanang, 5-iza-dC e theohile haholo mRNA maemong a DNMT3a le 3b ka mokhoa o khethehileng ho striatum (ESM Fig. 1a-d).

Motheong oa phuputso e fetileng e bontšang hore tekanyo ea mRNA ea DNMT1 e ne e laoloa hantle, bonyane karolong e itseng, ka nuclear nuclear ERRγ [], re ile ra hlahloba phello e ka bang teng ea γ-oryzanol mesebetsing ea ERRγ. Lisele tse ling tsa mammalian tseo e seng tsa batho li bontša hore li sebetsa ka matla ERRγ, 4-hydroxy tamoxifen, e leng agonist e matla ka ho fetisisa ea ERRγ, e fokotsehileng haholo mosebetsi oa ERRγ. Ka hloko, γ-oryzanol e fokotsa karolo e itseng ea ERRγ (hoo e ka bang ho fokotsa 40% ea bohlokoa ba innate) (setšoantšo sa Fig. (Fig.3a) .3a). Habohlokoa, ERRγ e ne e hlalositsoe haholo ho striatum empa e se hypothalamus (sa fe. (Fig.3b-d) .3b-d). Ho fapana le boemo ba striatum, γ-oryzanol e eketsa haholo liprotheine tsa DNMT1 feela ho hypothalamus (sa fe. (Fig.2k, 2k, l). Liphetho tsena li ka hlalosoa, bonyane karoloana, ka ho fumana hore STAT3A, molao o nepahetseng oa lekala la DNMT1 [], e ne e hlalositsoe ka bongata ho hypothalamus empa e se ka har'a statum (sa feiga. (Fig.33e-g).

Feie. 3 

Tšusumetso ea γ-oryzanol mesebetsing ea ERRγ le STAT3A. (a) Tšusumetso e thibelang ea γ-oryzanol ho ERRγ in vitro. Mesebetsi ea likarolo tsa ERRγ le li-ERyγ (γ-oryzanol (li-circular), acid e tala ...

Ho tsoela pele ho hlahloba tšusumetso ea γ-oryzanol mosebetsing oa DNMTs in vivo, ho thehoa ha SAH, e leng sehlahisoa sa DNA methylation le se nang le matla a ho thibela li-DNMTs, ho ile ha hlahlojoa litoeba tsa γ-oryzanol tse tšoaroang ke HFD. Ho ne ho se na liphetoho tse kholo ho sebopeho sa SAH ho sa tsotellehe statum kapa hypothalamus lipakeng tsa HFD-fepa le litlolo tse fepehileng (Fig. (Fig.2f, 2f, j). Ka ho hlakileng, γ-oryzanol e theohile haholo tlhahiso ea SAH ka striatum (Fig. (Fig.2f) 2f) empa eseng hypothalamus (sa feiga. (Fig.2j), 2j), ho fana ka maikutlo a hore γ-oryzanol e ka thibela mosebetsi oa DNMTs ka mokhoa o itseng oa striatum ho litoeba tse fepehileng ka HFD.

Ho hlahlojoa ha li-enzymatic ka thepa ea ho thibela li-γ-oryzanol bakeng sa DNMTs in vitro

Ka mor'a moo re ile ra hlahloba phello ea γ-oryzanol mosebetsing oa DNMTs in vitro. Mekhoa e sa thibeleng ea γ-oryzanol, acid e tala, 5-aza-dC, haloperidol (moemeli oa D2R), quinpirole (moemeli oa D2R agonist) le SAH khahlanong le DNMTs ba ile ba hlahlojoa. E le tšireletso e nepahetseng, SAH e ile ea thibela mesebetsi ea DNMTs ka mokhoa o itšetlehileng ka tekanyo ea meriana (Fig. (Fig.4a-f) .4a-f). Joalokaha ho ne ho lebeletsoe, haloperidol le quinpirole ha li na phello mesebetsing ea DNMTs (ESM Fig. 2). Ka ho hlakileng, γ-oryzanol e thibela haholo mesebetsi ea DNMT1 (IC50 3.2a μmol / l50 = 22.3 μmol / l) le 3b (thibelo e kholo ea 57%) (sa feiga. (Fig.4d-f) .4d-f). Ka lehlakoreng le leng, mosebetsi o thibelang oa acid e nang le metabolite ea γ-oryzanol, e ne e le tlase ho feta ea γ-oryzanol (Fig. (Fig.44d-f).

Feie. 4 

Tšusumetso e thibelang e-yyyzanol ho DNMTs in vitro. Litlhahlobo tsa ho hlahloba lintlha tse phahameng bakeng sa ba ka 'nang ba inhibitors ba DNMT1 (a), DNMT3a (b) le DNMT3b (c). Lintho tse ka thibeloang khahlanong le DNMTs bakeng sa γ-oryzanol, acid e nkiloeng (e-oryzanol ea metabolite), ...

Re ile ra tsoela pele ho batlisisa matlotlo a ho thibela aγ-oryzanol ho DNMTs. Sebopeho sa SAH se lekantsoe ho hlahloba mosebetsi o thibelang oa γ-oryzanol ho DNMTs in vitro. Lintlha tse mabapi le sebopeho sa SAH nakong ea DNA ea DNMT-mediated methylation li bontša mokhoa oa saturable oa Michaelis-Menten kinetics bakeng sa boteng le ho ba sieo ha γ-oryzanol (Fig. (Fig.4g-i) .4g-i). DNA methylation ea DNMT1, Eadie-Hofstee tlhahlobo e bontšitse hore γ-oryzanol ha e bontše liphello holim'a V , max ea sebopeho sa SAH (koloi, 597 pmol / min; γ-oryzanol 2 μmol / l, 619 pmol / min; γ-oryzanol 20 μmol / l, 608 pmol / min), ha ho bonahala γ-oryzanol e ekelitse K m (koloi, 0.47 μg / ml; γ-oryzanol 2 μmol / l, 0.67 μg / ml; γ-oryzanol 20 μmol / l, 0.89 μg / ml) (sa feiga. (Fig.4j) .4j). Liphetho tsena li bontša hore oryzanol ea yy e thibela DNMT1 bonyane karolong ea tlhōlisano. Ka lehlakoreng le leng, bakeng sa DNA ea DNMT3- le 3b-mediated methylation, γ-oryzanol e theohile V , max ea sebopeho sa SAH (DNMT3a: koloi, 85.3 pmol / min; γ-oryzanol 2 μmol / l, 63.1 pmol / min; γ-oryzanol 20 μmol / l, 42.5 pmol / min; DNMT3b: koloi, 42.3 pmol / min; γ -oryzanol 2 μmol / l; 28.0 pmol / min, γ-oryzanol 20 μmol / l, 15.0 pmol / min) mme, ka mokhoa o ts'oanang, K m bakeng sa karabelo ena (DNMT3a: koloi, 0.0086 μg / ml; γ-oryzanol 2 μmol / l, 0.0080 μg / ml; γ-oryzanol 20 μmol / l, 0.0058 μg / ml; DNMT3b: koloi, 0.0122 μg / ml; γ- oryzanol 2 μmol / l, 0.0097 μg / ml; γ-oryzanol 20 μmol / l, 0.0060 μg / ml) (feiga. (Fig.4k, 4k, l). Liphetho tsena li bontša hore oryzanol ea yy e thibela DNMT3a le 3b bonyane karolo e seng ea tlhōlisano.

γ-oryzanol e eketsa litekanyetso tsa D2R ka statum ea litoeba tse fepang HFD

Ka mor'a moo re ile ra leka monyetla oa hore γ-oryzanol e ka eketsa diteng tsa D2R tse hlaselang ka ho thibela DNMTs. Metsong e fepehileng ea HFD, tsamaiso ea molomo oa γ-oryzanol e fokolitse haholo DNA ea methylation e hlaselang sebakeng sa D2R (Fig. (Fig.5a), 5a), empa ha ea ka ea etsa sena hypothalamus (sa feiga. (Fig.5f) .5f). Ho ea ka liphuputso tsena, mRNA le litekanyetso tsa protheine tsa D2R li ile tsa eketseha ka makhetlo (Fig. (Fig.5b, 5b, g, k, l). Tšoanang le lintlha tsa phekolo le 5-aza-dC (sa feiga. (Fig.1), 1), ho ne ho se na liphello tse hlakileng ho RNA le liprotheine Drd1, Th 'me Slc6a3 (DAT) ho striatum, mme ha ho liphello ho maemo a Drd1, Th 'me Slc6a3 ho hypothalamus (sa feiga. (Fig.5c-e, 5c-e, h-k, m).

Feie. 5 

Ho thibela li-DNMTs ke γ-oryzanol e thibela khetho ea HFD ka ho eketseha ha li-D2R ha ho etsoa litoeba tsa HFD. DNA ea methylation maemong a khothalletsang sebaka sa D2R ka striatum (n = 3) (a) le hypothalamus ...

Liphuputso tse fetileng li bontšitse hore litekanyetso tsa D2R le DNMT1 li laoloa ke khatello ea ER le ho ruruha bonyane karolo e itseng ka NF-κB [, , ]. Ka hona re hlahlobile litekanyetso tsa liphatsa tsa lefutso tse amanang le khatello ea kelello ea ER le ho ruruha. Joalokaha ho bontšitsoe pejana [], HFD e eketsehile polelo ea liphatsa tsa lefutso tse kentseng TNF-α (Tnfa), monocyte chemoattractant protein-1 (MCP-1) (Ccl2), C / EBP homologous protheine (Khaola), ER-sebaka sa DnaJ 4 (ERdj4) (Dnajb9) le sebopeho sa X-box se kopantseng protheine 1 (Xbp1s) ho hypothalamus empa eseng ka striatum (sa feiga. (Fig.6) .6). Ka ho hlakileng, tlatsetso ea HFD le γ-oryzanol e fokotseha haholo ponts'o e fetisitsoeng ea Ccl2, Khaola, Dnajb9 'me Xbp1s feela ho hypothalamus empa eseng ka striatum (sa feiga. (Fig.66).

Feie. 6 

Tlhaloso ea liphatsa tsa lefutso tse amanang le khatello ea kelello le ea ER ka statum le hypothalamus. Litekanyo tsa mRNA bakeng sa Tnfa (a, f), Ccl2 (b, g), Khaola (c, h), Dnajb9 (d, i), le sebōpeho se entsoeng ka mafolofolo Xbp1 (Xbp1s) (e, j) ho striatum (n = 8) ...

Puisano

Ntho e ka sehloohong e fumanoang thuputsong ea hona joale ke hore γ-oryzanol e sebetsa e le DNMT e nang le matla a ho thibela likokoana-hloko, ka tsela e itseng e hlokomoloha, karolo e 'ngoe, khetho ea HFD ka mokhoa oa epigenetic oa D2R ea hlaselang. Ka striatum ea litoeba tse feptjoang ke HFD, litekanyetso tsa D2R li ne li fokotseha haholo, athe tse ling tsa D1R, TH le DAT ha lia fetoha (setšoantšo sa Fig. (Fig.1b-e, 1b-e, k-m). Litlaleho tsena li lumellana le maikutlo a hore ho senyeha ha D2R e hlaselang ho phetha karolo ea bohlokoa ho tsepameng mohopolo oa lijo ha o le HFD, e leng se lebisang ho feta hadonic ea HFD liphoofolong tse ngata haholo []. Thupong ea hona joale, phekolo ea litoeba tse feptjoang ka HFD le 5-aza-dC li eketsehile haholo maemong a ho hlasela D2R (setšoantšo sa Fig. (Fig.1b, 1b, k, l) mohlomong ka ho fokotseha ha methapo ea methylation ea DNA sebakeng sa D2R (Fig. (Fig.1a), 1a), 'me ka lebaka leo a hlokomoloha khetho ea mafura a lijo (setšoantšo sa feiga. (Fig.1n) .1n). Tlhaloso ena e boetse e tšehetsa karolo ea bohlokoa ea li-D2R tse hlaselang ka palo ea mantlha ha ho na le moputso oa lijo ha ho na le HFD.

Tlhahlobo ea rona ea in vitro e bonts'itse hore mosebetsi o thibelang oa γ-oryzanol khahlanong le DNMTs o ne o le matla ho feta oa methapo ea eona e matla ea metabolite (Fig. (Fig.4d-f), 4d-f), ho fana ka maikutlo a bohlokoa ba sebopeho se feletseng sa γ-oryzanol bakeng sa tšebetso ea eona ea ho thibela DNMTs. Lihlahisoa tsa rona tsa HFD, liphuputso tsa rona li bontša hore, kamora 'tsamaiso ea molomo, γ-oryzanol e fihla bokong e le sebopeho se feletseng' me e fokotsa litekanyetso le liketso tsa DNMTs ka mokhoa o khethollang haholo ka statum, ka lebaka la ho fokotseha ha methylation ea DNA sebakeng seo D2R ho striatum. Ho feta moo, lipatlisiso tsa rona tsa vitro li bontšitse hore γ-oryzanol e sebetsa e le mohanyetsi ka mofuthu khahlanong le ERRγ, e sebetsang ka ho khetheha e le tsamaiso e ntle ea tlhahiso ea DNMT1 [], ka hona e fokotsa mosebetsi oa DNMT1 (sa feiga. (Fig.3a) .3a). Tlhokomeliso, ERRγ e ne e hlalositsoe ka ho fetisisa ho striatum empa e se hypothalamus ka litoeba (sa feiga. (Fig.3b) .3b). Lintlha tsena li bontša hore γ-oryzanol e na le monyetla oa ho fokotsa lekala la mRNA la DNMT1, bonyane karoloana, ka thibelo ea ERRγ. Ho fapana le striatum, γ-oryzanol ha e bontše phello ka tekanyo ea D2R ho hypothalamus ho tswa ho litoeba tsa HFD (Fig. (Fig.5g, 5g, k, l).

Ka lehlakoreng le leng, re bontsitse hore γ-oryzanol e eketseha haholo maemong a DNMT1 ho hypothalamus empa eseng ka striatum (sa feiga. (Fig.2k, 2k, l). Ho bontšitsoe hore STAT3 e eketsa lintho tsa DNMT1 lisele tse kotsi tsa T-lymphoma []. Ka ho hlakileng, re kile ra bontša hore γ-oryzanol e eketsa haholo phosphorylation e bakoang ke leptin e bakoang ke leptin ho hypothalamus ho tswa ho litoeba tsa HFD []. Hape hoa lokela ho hlokomeloa hore STAT3A e ne e hlalositsoe haholo ho hypothalamus empa eseng ka statum ho litoeba (sa feiga. (Fig.3e-g) .3e-g). Dintlha tsena li re leka ho nahana hore phapang e hlahang e le hantle ea γ-oryzanol ka mekhahlelo ea DNMT1 pakeng tsa hypothalamus le striatum e ka boleloa, bonyane karolo e itseng, ho tse ling tse itseng tsa sebaka sa STAT3A le ERRγ bokong ba litoeba ( Feie. (Fig.3b-g) .3b-g). Ka kakaretso, ho bonahala eka ho na le mokhoa o tšoanang oa ho bontša ERRγ le STAT3A pakeng tsa striatum le hypothalamus ka litoeba. Motheong oa liphetho tsa rona, ke ka lebaka le utloahalang ho nahana hore ka striatum, moo tlhahiso ea ERRγ e ngata, γ-oryzanol e ka theola mokhoa oa mRNA le ts'ebetso ea enzyme ea DNMT1 e le mohloli o fosahetseng oa ERRY. Ka lehlakoreng le leng, ho hypothalamus, moo STAT3α e hlahisang teng, γ-oryzanol e ka eketsa maemo a DNMT1 ka mokhoa o khethehileng.

Phuputso ea morao-rao e bontšitse hore ho hlokomoloha pontšo ea ho bolaea D2R e bakoang ke HFD e senya boitšoaro ba ho fepa [], ho fana ka maikutlo a hore bohlokoa ba bohlokoa ba thibelo ea DNMTs e tsoaloang ke ea bohlokoa bakeng sa phekolo ea botenya. Ka lehlakoreng le leng, phuputso e fetileng e bontšitse hore ho ka etsahala hore boemo ba DNA methylation ea liphatsa tsa melanocortin liphatsa tsa lefutso tsa 4 tse hlalositsoeng ka nuclei e khethehileng e ka etsa hore mefuta e meng ea boikhohomoso ba botenya e be boemong bo botle ba mahlaseli a mosehla []. Le hoja liphuputso tse ling li hlokehile ho hlakola mekhoa ea motheo, liphuputso tsena li bonts'a bohlokoa ba DNA methylation ea liphatsa tsa lefutso, ea liphatsa tsa lefutso le ea ho latellana ka pathophysiology ea botenya bo bakoang ke HFD.

Re sa tsoa tlaleha hore HFD e ekelitse boemo ba D2R lihlekehlekeng tsa pancreatic tsa litoeba [, ]. Ho ka 'na ha e-ba le hore augmentation e joalo e nahanngoa, bonyane karolo e itseng, ke khatello ea ER le ho ruruha ka NF-κB, hobane ho na le lintho tse' maloa tse amohelang NF-κB sebakeng sa Promoter sa D2R [, ]. Ho feta moo, lipatlisiso tsa morao-rao li bontšitse hore TNF-α le IL-1β li eketsa boemo le ts'ebetso ea DNMT1 ka mahlaseli adipose ho tswa ho litoeba tse fepehileng tsa HFD []. Habohlokoa, phuputso ea hona joale e bontšitse hore khatello ea HF e bakoang ke ER le ho ruruha ka mokhoa o khethehileng ka hypothalamus empa e seng ka striatum (Fig. (Fig.6) .6). Lisebelisoa tse tebileng tsa lisele tsa 'mele-sebaka, le sebaka se itseng sa DNA methylation le demethylation lipakeng tsa rona tsa liteko li lokela ho emisa lipatlisiso.

Hammoho le tlaleho ea rona ea pele e bontša hore γ-oryzanol e thibela khetho bakeng sa HFD ka taolo ea phekolo ea hypothalamic ea khatello ea ER mathateng [], γ-oryzanol e boetse e emela thepa e ikhethang ea ho ntlafatsa hadonic le khatello ea metsoli ea boitšoaro ba ho fepa. Hobane lithethefatsi tse ling tsa ho loantša likokoana-hloko tse hlahisitsoeng li tsebahala ho baka liphello tse bohloko tse bohloko [], tlhaho ea tlhaho ea lijo tsa tlhaho mabapi le tsamaiso ea boko ea boko e lebeletsoe ho phekola botenya-lefu la tsoekere la boloetse bo sireletsehileng []. Ka paradigm ena, γ-oryzanol ke mokhethoa ea tšoaetsanoang oa antiobesity o nang le thepa e khethehileng ea ho ba modulator ea epigenetic.

 

Lisebelisoa tsa elektronike tse tlatsetsang

 

ESM(256K, pdf) 

(PDF 256 kb)

Liteboho

Re leboha S. Okamoto (Univesithi ea Ryukyus, Japane) bakeng sa ho hlahloba buka eo. Re leboha M. Hirata, H. Kaneshiro, I. Asato le C. Noguchi (Univesithi ea Ryukyus, Japane) bakeng sa thuso ea mongoli.

khutsufalitsoeng

5-iza-dC5-aza-2'-deoxycytidine
D1RDopamine D1 receptor
D2RDopamine D2 receptor
DATDopamine transporter
DNMTDNA methyltransferase
EREndoplasmic reticulum
ERRMokelikeli o amanang le Estrogen
HFDLijo tse phahameng tsa mafura
SAHS-Adenosyl-l-homocysteine
SAMS-Adenosyl methionine
STAT3ATransducer ea letšoao le activator ea mongolo oa 3A
THTyrosine hydroxylase
 

Notes

Ho fumaneha ha data

Li-Datasets tse hlahisitsoeng le / kapa tse hlalositsoeng nakong ea thuto ea morao-rao li fumaneha ho tloha ho mongoli ea tšoanang ka likōpo tse utloahalang.

dithuso tsa ditjhelete

Mosebetsi ona o ne o tšehetsoa ka karolo e 'ngoe ka thuso ea lithuso tsa lithuso tsa Mokhatlo oa Japane bakeng sa Ts'ebeliso ea Saense (JSPS; KAKENHI Grant Numeri 15K19520 le 24591338), Lekhotla la Saense, Theknoloji le Theknoloji (CSTI), Lenaneo la Thuto-kholo ea Strategic Innovation Promotion Program (SIP) 'Theknoloji bakeng sa ho hlahisa temo e hlahlamang, meru le litlhapi', Lotte Foundation, Japane Foundation ea Applied Enzymology, New Energy le Industrial Technology Development Organization (NEDO), Project for Formation of Life Science Network (Pharmaceutical Field ) (Profinseng ea Okinawa, Japane) le Morero oa Tsoelo-pele oa Phekolo ea Bongaka ea Puso ea Okinawa, Japane, hammoho le thuso ea Profinseng ea Okinawa bakeng sa ho ntšetsa pele meriana e tsoetseng pele (Puso ea Okinawa, Japane).

Bobeli ba thahasello

Bangoli ba bolela hore ha ho na botho ba thahasello bo amanang le buka ena e ngotsoeng ka letsoho.

Polelo ea liphallelo

CK le HM li entse lipatlisiso. CK le TK ba ile ba etsa liteko tseo ba li hlahloba. TK, CS-O, CT, MT, MM le KA li tlatsetsa ho hlalosang dintlha. CK le HM ba ngotse mongolo o ngotsoeng ka letsoho. Bangoli bohle ba tlatselitse tlhaloso ea data. Bangoli bohle ba ile ba ikopanya ho hlahloba mongolo o ngotsoeng ka letsoho le ho amohela phetolelo ea eona ea ho qetela. HM ke guarantor ea mosebetsi ona, o na le phihlelo e feletseng ea boitsebiso bohle mme o nka boikarabelo bo feletseng bakeng sa botšepehi ba data le ho nepahala ha tlhahlobo ea data.

Mongolo o botlaaseng ba leqephe

 

Lisebelisoa tsa elektronike tse tlatsetsang

Phetolelo ea inthanete ea sehlooho sena (etsa: 10.1007 / s00125-017-4305-4) e na le boitsebiso bo hlophisitsoeng ka lithaka empa bo sa sebelisoe, bo fumanehang ho basebelisi ba nang le matla.

 

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