Doorarka Kala Duwan ee Jidhka Ketone

Jidhka Ketone waxaa abuuray beerka waxaana loo isticmaalaa il tamar marka gulukoosku aanu si sahal ah ugu jirin jidhka bini'aadamka. Labada ketone ee ugu muhiimsan waa acetoacetate (AcAc) iyo 3-beta-hydroxybutyrate (3HB), halka acetone uu yahay kan saddexaad oo ugu yar, ketone jirka. Ketones had iyo jeer waxay ku jiraan dhiigga heerarkooduna wuu kordhaa xilliga soonka iyo jimicsiga dheerKetogenesis waa habka biochemical ee ay nooluhu u soo saaraan jidhka ketone iyaga oo u maraya burburka asiidhka dufanka leh iyo amino acids ketogenic.

Jidhka ketone ayaa inta badan laga soo saaraa mitochondria ee unugyada beerka. Ketogenesis waxay dhacdaa marka ay jiraan heerar gulukoos oo hooseeya ee dhiiga, gaar ahaan ka dib marka kaydka karbohaydraytyada gacanta, sida glycogen, ay daalan yihiin. Habkani waxa kale oo uu iman karaa marka ay jiraan qadar ku filan oo insulin ah. Soo saarista maydadka ketone ayaa ugu dambeyntii la bilaabay si loo sameeyo tamar la heli karo oo ku kaydsan jidhka bini'aadamka sida acids dufanka leh. Ketogenesis wuxuu ku dhacaa mitochondria halkaas oo si madax-bannaan loo habeeyo.

aan la taaban karin

Dheef-shiid kiimikaad ee ketone waa udub dhexaadka u ah homeostasis physiological. Dib-u-eegisgan, waxaanu kaga hadlaynaa sida ketones ugu adeego doorarka dheef-shiid kiimikaadka hagaajinta wanaagsan ee hagaajinaya xubinta iyo waxqabadka noolaha ee hadhaaga nafaqo ee kala duwan kana ilaalinaya bararka iyo dhaawaca hababka xubnaha badan. Dhaqan ahaan waxaa loo arkaa inay yihiin substrate-ka dheef-shiid kiimikaadka oo kaliya ee lagu qoray xaddidaadda karbohaydraytyada, indha-indheyntii dhawaa waxay hoosta ka xariiqday muhiimada ay leedahay jirka ketone sida dhexdhexaadiyeyaasha muhiimka ah ee dheef-shiid kiimikaadka iyo calaamadaynta marka karbohaydraytyadu ay badan yihiin. Dhameystirka dib u habeynta xulashooyinka daweynta ee loo yaqaan cudurada habka dareemayaasha, doorarka mustaqbalka ee jirka ketone ee kansarka ayaa soo baxay, sida doorarka ilaalinta xiisaha leh ee wadnaha iyo beerka, furitaanka xulashooyinka daweynta ee buurnaanta la xiriirta iyo cudurada wadnaha. Khilaafaadka dheef-shiid kiimikaadka ketone iyo calaamadaynta ayaa laga wada hadlay si loo heshiiyo dogma qadiimiga ah iyo indho-indheynta casriga ah.

Hordhac

Jidhka Ketone waa ilo shidaal dheef-shiid kiimikaad oo muhiim u ah dhammaan qaybaha nolosha, eukarya, bakteeriyada, iyo archaea (Aneja et al., 2002; Cahill GF Jr, 2006; Krishnakumar et al., 2008). Dheef-shiid kiimikaadka jirka ee ketone ee bini'aadamka ayaa loo faa'ideeyay inuu shido maskaxda inta lagu jiro xilliyada xasaasiga ah ee nafaqo-xumada. Jidhka Ketone waxa ku xidhan dariiqooyinka dheef-shiid kiimikaad ee naasleyda ah sida ?-oxidation (FAO), wareegga tricarboxylic acid (TCA), gluconeogenesis, de novo lipogenesis (DNL), iyo biosynthesis of sterols. Naasleyda, jirka ketone waxaa inta badan laga soo saaraa beerka laga bilaabo FAO-ka-soo-baxa acetyl-CoA, waxaana loo raraa unugyo ka baxsan cagaarshowga si loo soo saaro oksaydhka. Cilmi-nafsigan wuxuu bixiyaa shidaal kale oo lagu kordhiyo waqtiyo kooban oo soonka, taasoo kordhisa helitaanka aashitada dufanka leh waxayna yaraynaysaa helitaanka karbohaydrayt (Cahill GF Jr, 2006; McGarry iyo Foster, 1980; Robinson iyo Williamson, 1980). oksaydhaynta jidhka Ketone waxa ay noqotaa qayb muhiim ah oo ka mid ah dheef-shiid kiimikaadka naasleyda tamarta ee gudaha unugyada ka baxsan xubnaha jirka ee tiro badan oo ah dawlado jireed, oo ay ku jiraan soonka, gaajada, xilliga dhalmada, jimicsiga ka dib, uurka, iyo u hoggaansanaanta cuntooyinka karbohaydraytyada hooseeya. Isku darka wadarta guud ee uruurinta jirka ketone ee dadka qaangaarka ah ee caafimaadka qaba waxay caadi ahaan muujiyaan wareegga wareegga inta u dhaxaysa qiyaastii 100 ~ 250 �M, kor u kaca ~ 1 mM ka dib jimicsiga dheer ama 24h ee soonka, waxayna ku ururin kartaa ilaa 20 mM gobolada cudurada sida ketoacidosis sonkorowga. Cahill GF Jr, 2006; Johnson et al., 1969b; Koeslag et al., 1980; Robinson iyo Williamson, 1980; Wildenhoff et al., 1974). Beerka bini'aadamku wuxuu soo saaraa ilaa 300 g oo ah jirka ketone maalintii (Balasse iyo Fery, 1989), taas oo gacan ka geysata inta u dhaxaysa 5% wadarta kharashka tamarta ee quudinta, sooman, iyo dawladaha gaajada (Balasse et al., 20; Cox et al. al., 1978).

Daraasadihii ugu dambeeyay waxay hadda muujinayaan doorka lama huraanka ah ee jirka ketone ee dheef-shiid kiimikaadka unugyada naasleyda, homeostasis, iyo calaamadeynta hoos timaada noocyo badan oo jireed iyo xaalado jireed. Marka laga reebo u adeegida tamarta tamarta unugyada kabaxsan sida maskaxda, wadnaha, ama muruqa lafaha, jidhka ketone wuxuu ka ciyaaraa door muhiim ah sida dhexdhexaadiyeyaasha calaamadaha, darawalada wax ka beddelka borotiinka post-translational (PTM), iyo modulators caabuqa iyo walbahaarka oksaydhka. Dib-u-eegisgan, waxaanu ku bixinaynaa labadaba aragtiyo qadiimi ah iyo kuwa casriga ah ee doorarka pleiotropic ee jidhka ketone iyo dheef-shiid kiimikaadkooda.

Dulmar guud ee dheef-shiid kiimikaadka Jidhka Ketone

Heerka ketogenesis cagaarshow waxaa maamula taxane la habeeyay oo isbeddellada jireed iyo kiimikaad ee dufanka. Nidaamiyeyaasha aasaasiga ah waxaa ka mid ah lipolysis of acids fatty from triacylglycerol, gaadiidka iyo guud ahaan xuubka plasma hepatocyte, gaadiidka galay mitochondria iyada oo loo marayo carnitine palmitoyltransferase 1 (CPT1), ?-oxidation spiral, dhaqdhaqaaqa wareegga TCA iyo uruurinta dhexdhexaadka ah, dib-u-celinta awoodda, iyo xakameynaya hormoonnada. hababkaas, oo u badan glucagon iyo insulin [dib loo eegay (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al., 1983; Kahn et al., 2005; McGarry iyo Foster) , 1980; Williamson iyo al., 1969). Ketogenesis-ka caadiga ah waxaa loo arkaa inuu yahay dariiq daadsan, kaas oo ?-oxidation-derived acetyl-CoA uu dhaafo dhaqdhaqaaqa citrate synthase iyo/ama helitaanka oxaloacetate ee uumi si loo sameeyo citrate. Dhexdhexaadiyeyaasha saddexda-carbon waxay soo bandhigaan waxqabad ka-hortagga ketogenic, oo loo maleynayo inay sabab u tahay awoodda ay u leeyihiin inay ballaariyaan barkadda oxaloacetate ee isticmaalka acetyl-CoA, laakiin cagaarshowga acetyl-CoA kaligiis ma go'aamiyo heerka ketogenic (Foster, 1967; Rawat iyo Menahan, 1975; Williamson). iyo al., 1969). Nidaaminta ketogenesis ee hoormoonka, qoraallada, iyo dhacdooyinka tarjumaada ka dib ayaa si wada jir ah u taageeraya fikradda ah in hababka molecular ee hagaajinta heerka ketogenic ay weli tahay mid aan si dhammaystiran loo fahmin (eeg Xeerka HMGCS2 iyo SCOT/OXCT1).

Ketogenesis wuxuu ugu horrayn ku dhacaa matrix mitochondrial hepatic marka loo eego heerar u dhigma wadarta oksaydheynta dufanka. Ka dib markii la qaado silsiladaha acyl ee xuubabka mitochondrial iyo ?-oxidation, isoform-ka mitochondrial ee 3-hydroxymethylglutaryl-CoA synthase (HMGCS2) waxay kicisaa qaddarka samaynta uumiga acetoacetyl-CoA (AcAc-CoA) iyo acetyl-CoA si loo dhaliyo HMG-CoA (Jaantuska. 1A). HMG-CoA lyase (HMGCL) waxay jebisay HMG-CoA si ay u xorayso acetyl-CoA iyo acetoacetate (AcAc), kan dambena waxa lagu dhimay d-?-hydroxybutyrate (d-?OHB) by phosphatidylcholine-ku-tiirsanaanta mitochondrial d-?OHB dehydrogenase BDH1) ee NAD+/NADH-ku-xidhay falcelinta isu-dheellitirnaanta dhow (Bock iyo Fleischer, 1975; LEHNINGER et al., 1960). Miisaanka BDH1 wuxuu si joogta ah u jecel yahay d-? OHB soosaarka, laakiin saamiga AcAc / d-? Williamson iyo al., 1). AcAc waxa kale oo ay si iskiis ah u decarboxylate u noqon kartaa acetone (Pedersen, 1969), isha urta macaan ee bini'aadamka qaba ketoacidosis (ie, wadarta jirka ketone serum> ~1967 mM; AcAc pKa 1929,?OHB pKa 7). Hababka loo maro maydadka ketone ee lagu qaado xuubka gudaha mitochondrial lama yaqaan, laakiin AcAc/d-?OHB waxaa laga sii daayaa unugyada iyada oo loo sii marayo gaadiidleyda monocarboxylate (naasleyda, MCT 3.6 iyo 4.7, oo sidoo kale loo yaqaanno side solute 1A xubnaha qoyska 2 iyo 16) oo loo raro wareegga wareegga unugyada hepatic ee loogu talagalay oksaydhka terminal (Cotter et al., 1; Halestrap iyo Wilson, 7; Halestrap, 2011; Hugo et al., 2012). Isku-duubnaanta meeraha ketone ee wareegaya ayaa ka sarreeya kuwa ku jira unugyada hepatic-ka (Harrison iyo Long, 2012) taasoo tilmaamaysa in maydadka ketone la soo dejiyo si tartiib tartiib ah. Isbeddellada shaqada ee lumay ee MCT2012 waxay la xidhiidhaan ketoacidosis-ka ketoacidosis, taas oo soo jeedinaysa doorka muhiimka ah ee soo dejinta jidhka ketone.

� Marka laga reebo u leexinta suurtagalka ah ee maydadka ketone-ka oo loo beddelo qaddar aan-oxidative ahayn (eeg qaddarka dheef-shiid kiimikaadka aan oksaydhiyaha ahayn ee jidhka ketone), hepatocytes ayaa ka maqan awoodda ay ku dheef-shiidaan jidhka ketone ee ay soo saaraan. Jidhka Ketone ee lagu sameeyay de novo beerka ayaa ah (i) catabolized in mitochondria ee unugyo hepatic ka baxsan ilaa acetyl-CoA, kaas oo diyaar u ah wareegga TCA ee oksaydhka terminal (Jaantus. 1A), (ii) loo leexiyo lipogenesis ama sterol synthesis waddooyinka Jaantuska 1B), ama (iii) oo kaadida laga soo saaray. Sida shidaalka tamarta kale, jidhka ketone ayaa si aad ah u oksaydhsan wadnaha, murqaha lafaha, iyo maskaxda (Balasse iyo Fery, 1989; Bentourkia et al., 2009; Owen et al., 1967; Reichard et al., 1974; Sultan, 1988 ). Mitochondrial Extrahepatic Extrahepatic BDH1 waxay kicisaa falcelinta ugu horraysa ee OHB oksaydhation, oo u beddesha dib AcAc (LEHNINGER et al., 1960; Sandermann et al., 1986). cytoplasmic d-?OHB-dehydrogenase (BDH2) oo leh 20% aqoonsiga isku xigxiga ee BDH1 ayaa leh Km sare ee jirka ketone, sidoo kale wuxuu door ka ciyaaraa homeostasis birta (Davuluri et al., 2016; Guo et al., 2006) . Matrix mitochondrial ka baxsan hepatic, AcAc waxa lagu hawlgeliyay AcAc-CoA iyada oo la beddelanayo CoA-moiety ka succinyl-CoA falcelin ay kicisay naasleyda u gaarka ah CoA wareejinta, succinyl-CoA: 3-oxoacid-CoA wareejinta (SCOT, CoA wareejinta; waxaa codeeyay OXCT1), iyada oo loo marayo falcelin dheellitiran oo dhow. Tamarta bilaashka ah ee lagu sii daayo hydrolysis ee AcAc-CoA way ka weyn tahay ta succinyl-CoA, iyada oo door bidaaya samaynta AcAc. Markaa ketone jidhku oksidhifeedka qulqulka wuxuu ku dhacaa ficil baaxad leh: sahay badan oo AcAc ah iyo isticmaalka degdega ah ee acetyl-CoA iyada oo loo marayo citrate synthase waxay door bidaa samaynta AcAc-CoA (+ succinate) ee SCOT. Waxaa xusid mudan, marka la barbardhigo gulukooska (hexokinase) iyo acids dufanka leh (acyl-CoA synthetases), firfircoonida jirka ketone (SCOT) ee qaab oksaydhism ah uma baahna maalgelinta ATP. Dareen-celinta thiolase AcAc-CoA ee la beddeli karo [oo ay kacday mid ka mid ah afarta thiolases ee mitochondrial oo ay ku dhejiyeen midkood ACAA2 (ku dhejinta enzyme loo yaqaan T1 ama CT), ACAT1 (encoding T2), HADHA, ama HADHB] waxay soo saartaa laba unug oo ah acetyl-CoA, kuwaas oo gala wareegga TCA (Hersh iyo Jencks, 1967; Stern et al., 1956; Williamson et al., 1971). Inta lagu jiro gobolada ketotic (ie, wadarta guud ee ketones> 500 �M), jidhka ketone waxa ay noqdaan kuwa wax ku biiriya kharashaadka tamarta waxaana si degdeg ah looga isticmaalaa unugyadu ilaa inta la qaadanayo ama buuxinta oksaydhisku ay dhacayso (Balasse et al., 1978; Balasse iyo Fery, 1989 Edmond iyo al., 1987). Qayb aad u yar oo ka mid ah jidhka ketone ee beerka ka soo baxa ayaa si sahal ah loogu cabbiri karaa kaadida, iyo ka faa'iidaysiga iyo dib u nuugista kelyuhu waxay u dhigantaa wareegga wareegga (Goldstein, 1987; Robinson iyo Williamson, 1980). Inta lagu jiro xaaladaha ketotic ee aadka u sarreeya (> 1 mM ee plazma), ketonuria waxay u adeegtaa sidii wariye-yare-tire oo ketosis ah, in kasta oo inta badan baaritaannada kiliinikada ee unugyada ketone kaadida ay ogaadaan AcAc laakiin maaha?OHB (Klocker et al., 2013).

Substrate-ka Ketogenic iyo Saamaynta ay ku leeyihiin dheef-shiid kiimikaadka Hepatocyte

Qaybaha Ketogenic waxaa ka mid ah asiidh dufan iyo amino acids (Jaantus. 1B). Catabolism-ka amino acids, gaar ahaan leucine, waxay abuurtaa qiyaastii 4% jirka ketone ee xaalad nuugista ka dib (Thomas et al., 1982). Markaa barkada substrate acetyl-CoA si ay u soo saarto maydadka ketone ayaa inta badan ka soo baxa acids dufanka leh, sababtoo ah inta lagu jiro gobolada sahayda karbohaydrayt ee la yareeyay, pyruvate waxay gashaa wareegga cagaarshow TCA ugu horrayn iyada oo loo marayo anaplerosis, ie, karboksylation-ku-tiirsanaanta ATP ee oxaloacetate (OAA), ama malate. (MAL), oo aan ahayn decarboxylation oksaydhiyaha ilaa acetyl-CoA (Jeoung et al., 2012; Magnusson et al., 1991; Merritt et al., 2011). Beerka, gulukooska iyo pyruvate waxay gacan ka geystaan ​​​​ketogenesis, xitaa marka pyruvate decarboxylation ilaa acetyl-CoA ay tahay ugu badnaan (Jeoung et al., 2012).

Acetyl-CoA waxay hoos timaadaa doorar dhowr ah oo udub dhexaad u ah dheef-shiid kiimikaadka dhexdhexaadka ah ee ka baxsan jiilka ATP iyada oo loo marayo oksaydhka terminal (sidoo kale eeg isdhexgalka dheef-shiid kiimikaadka jidhka ketone, beddelka-tarjumaada ka dib, iyo physiology cell). Acetyl-CoA allosterically waxay u shaqeysaa (i) pyruvate carboxylase (PC), taas oo kicinaysa habka xakamaynta dheef-shiid kiimikaadka kaas oo kordhiya gelitaanka anaplerotic ee dheef-shiid kiimikaadka wareegga TCA (Owen et al., 2002; Scrutton iyo Utter, 1967) kinase, kaas oo fosfooraska ka hortagaya pyruvate dehydrogenase (PDH) (Cooper et al., 1975), taas oo sii wanaajinaysa socodka pyruvate ee wareegga TCA iyada oo loo marayo anaplerosis. Intaa waxaa dheer, cytoplasmic acetyl-CoA, oo barkaddeeda lagu kordhiyey habab u beddelaya mitochondrial acetyl-CoA si ay u noqdaan dheef-shiid kiimikaad la qaadi karo, waxay joojisaa oxidation dufanka: acetyl-CoA carboxylase (ACC) waxay kicisaa beddelka acetyl-CoA ilaa malonyl-CoA, substrate-ka lipogenic. iyo allosteric inhibitor of mitochondrial CPT1 [ dib loo eegay (Kahn et al., 2005; McGarry iyo Foster, 1980)]. Markaa, barkadda mitochondrial acetyl-CoA labadaba waxay nidaamisaa oo ay nidaamisaa dariiqa qulqulaya ee ketogenesis, kaas oo abaabula dhinacyada muhiimka ah ee dheef-shiid kiimikaad dhexdhexaad ah.

Dheef-shiid kiimikaad Aan Oxidative ahayn ee Jidhka Ketone

Masiirka ugu badan ee ketones-ka beerka ka soo baxa waa oksaydhaynta kabaxsan-hepatic-ku-tiirsan SCOT. Si kastaba ha ahaatee, AcAc waxaa laga dhoofin karaa mitochondria waxaana loo isticmaali karaa waddooyinka anabolic iyada oo loo beddelayo AcAc-CoA falcelinta ku-tiirsanaanta ATP ee ay kiciso cytoplasmic acetoacetyl-CoA synthetase (AACS, Fig. 1B). Dariiqani waa mid firfircoon inta lagu jiro korriinka maskaxda iyo qanjidhada naaska nuujinta (Morris, 2005; Robinson iyo Williamson, 1978; Ohgami et al., 2003). AACS sidoo kale si aad ah ayaa loogu muujiyay unugyada adipose, iyo osteoclasts firfircoon (Aguilo et al., 2010; Yamasaki et al., 2016). Cytoplasmic AcAc-CoA waxaa ama hagi kara cytosolic HMGCS1 xagga sterol biosynthesis, ama la kala jejebiyey mid ka mid ah labada cytoplasmic thiolases acetyl-CoA (ACAA1 iyo ACAT2), carboxylated si malonyl-CoA, oo gacan ka synthesize of dufanka acids iyo Berg al., 1984; Edmond, 1974; Endemann iyo al., 1982; Geelen iyo al., 1983; Webber iyo Edmond, 1977).

Iyadoo muhiimada jir ahaaneed aan weli la dhisin, ketones waxay u adeegi kartaa substrates anabolic xitaa beerka. Xaaladaha tijaabada ah ee macmalka ah, AcAc waxay wax ku biirin kartaa ilaa kala badh lipid cusub oo la sameeyay, iyo ilaa 75% kolestaroolka cusub ee la sameeyay (Endemann et al., 1982; Geelen et al., 1983; Freed et al., 1988). Sababtoo ah AcAc waxaa laga soo qaatay oksaydheynta dufanka beerka ee aan dhamaystirnayn, awoodda AcAc si ay gacan uga geysato lipogenesis ee vivo waxay ka dhigan tahay baaskiil wadid aan faa'iido lahayn, halkaas oo ketones-dufanka laga helay loo isticmaali karo wax soo saarka dufanka, fikradda muhiimka ah ee jireed waxay u baahan tahay tijaabo tijaabo ah, laakiin waxay u adeegi kartaa doorarka la qabsiga ama laqabsiga (Solinas et al., 2015). AcAc waxay si xamaasad leh u siisaa cholesterogenesis, oo leh AACS Km-AcAc hooseeya (~ 50 �M) oo door bida firfircoonida AcAc xitaa gobolka la quudiyo (Bergstrom et al., 1984). Doorka firfircoon ee dheef-shiid kiimikaadka cytoplasmic ketone ayaa lagu soo jeediyay jiirka asaasiga ah ee embriyaha embriyaha iyo 3T3-L1-adipocytes-ka-soo-baxa, sida AACS garaacista kala duwanaanshaha nooc kasta oo unug ah (Hasegawa et al., 2012a; Hasegawa et al., 2012b). garaacista AACS ee jiirarka gudaha vivo waxay hoos u dhigtay kolestaroolka serum (Hasegawa et al., 2012c). SREBP-2, maamulaha transcriptional master of kolestarool biosynthesis, iyo proliferator proliferator receptor (PPAR) -? waa AACS firfircooniyaal qoraal ah, oo nidaamiya qoraalkeeda inta lagu jiro horumarka neurite iyo beerka (Aguilo et al., 2010; Hasegawa et al., 2012c). Isku soo wada duuboo, dheef-shiid kiimikaadka jirka ee cytoplasmic ayaa laga yaabaa inuu muhiim u yahay xaaladaha xulashada ama cudurada taariikhda dabiiciga ah, laakiin kuma filna in la tuuro jirka ketone ee beerka ka soo baxa, maadaama hyperketonemia weyn uu ku dhaco goobta daciifinta xulashada aasaasiga ah ee qaddarka oksaydhka iyada oo la luminayo isbeddellada shaqada. ilaa SCOT (Berry et al., 2001; Cotter et al., 2011).

Xeerarka HMGCS2 iyo SCOT/OXCT1

Kala duwanaanshaha mitochondrial ee hidda-sidaha cytosolic HMGCS wuxuu dhacay horaantii kobcinta laf dhabarta sababtoo ah baahida loo qabo in la taageero ketogenesis cagaarshow ee noocyada leh maskaxda sare ee miisaanka jidhka (Boukaftane et al., 1994; Cunnane iyo Crawford, 2003). Isbeddellada HMGCS2 ee shaqada lumay ee dabiiciga ah ee bini'aadamka waxay sababaan xad-dhaaf ah hypoketotic hypoglycemia (Pitt et al., 2015; Thompson et al., 1997). Muujinta adag ee HMGCS2 waxay ku xaddidan tahay hepatocytes iyo epithelium colonic, iyo muujinteeda iyo dhaqdhaqaaqa enzymatic waxaa la isku duway iyada oo loo marayo habab kala duwan (Mascaro et al., 1995; McGarry iyo Foster, 1980; Robinson iyo Williamson, 1980). Iyadoo baaxadda buuxda ee dawladaha jir ahaaneed ee saameeya HMGCS2 ay u baahan tahay faahfaahin dheeraad ah, muujinta iyo / ama dhaqdhaqaaqa ayaa la nidaamiyaa inta lagu jiro xilliga hore ee dhalmada, gabowga, sonkorowga, gaajada ama qaadashada cuntada ketogenic (Balasse iyo Fery, 1989; Cahill GF Jr, 2006 Girard iyo al., 1992; Hegardt, 1999; Satapati et al., 2012; Sengupta et al., 2010). Uurjiifka, methylation ee gobolka 5 ee garabka ee Hmgcs2 hiddo-wadaha ayaa si rogan ula xidhiidha qoraalkiisa, oo qayb ahaan waa loo rogaa dhalashada ka dib (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al ., 1983). Sidoo kale, cagaarshow Bdh1 wuxuu soo bandhigayaa qaabka korriinka korriinka, kor u kaca dhalashada ilaa naaska, iyo sidoo kale waxaa keena cuntada ketogenic ee habka koritaanka fibroblast (FGF) -21-ku-tiirsanaanta (Badman et al., 2007; Zhang et al., 1989). ). Ketogenesis ee naasleyda ayaa si aad ah uga jawaaba insulin iyo glucagon labadaba, la xakameeyo lana kiciyo, siday u kala horreeyaan (McGarry iyo Foster, 1977). Insulintu waxay xakameysaa lipolysis unug adipose ah, sidaas darteed waxay ka reebaysaa ketogenesis substrate-keeda, halka glucagon ay kordhiso qulqulka ketogenic iyada oo loo marayo saameyn toos ah beerka (Hegardt, 1999). Qorista Hmgcs2 waxaa kiciyay fargeeto fargeeto ah FOXA2, kaas oo lagu xannibay insulin-phosphatidylinositol-3-kinase/Akt, waxaana keenay calaamadda glucagon-cAMP-p300 (Arias et al., 1995; Hegardt, 1999. , 1990; Thumelin iyo al., 1993; von Meyenn iyo al., 2013; Wolfrum iyo al., 2004; Wolfrum iyo al., 2003). PPAR? (Rodriguez et al., 1994) oo ay weheliso bartilmaameedkeeda, FGF21 (Badman et al., 2007) sidoo kale waxay keenaysaa qoraalka Hmgcs2 ee beerka inta lagu jiro gaajada ama maamulka cuntada ketogenic (Badman et al., 2007; Inagaki et al., 2007) ). Soo saarista PPAR? waxaa laga yaabaa inay dhacdo ka hor inta aan laga soo wareegin uurjiifka ilaa physiology-ga dhallaanka, halka firfircoonida FGF21 laga yaabo in la doorbido xilliga dhalmada hore iyada oo loo marayo ?OHB-dhexdhexaadinta xannibaadda histone deacetylase (HDAC) -3 (Rando et al., 2016). mTORC1 (bartilmaameedka naasleyda ee dhismaha rapamycin 1) joojinta ku tiirsanaanta PPAR? Dhaqdhaqaaqa qoraalka ah sidoo kale waa maamulaha muhiimka ah ee muujinta hidda-wadaha Hmgcs2 (Sengupta et al., 2010), iyo beerka PER2, oscillator circadian master, si aan toos ahayn u habeeya muujinta Hmgcs2 (Chavan et al., 2016). Indho-indheynyadii dhawaa waxay muujinayaan in interleukin-6 ee buro-baxa ka-baxsan ay dhaawacdo ketogenesis iyada oo loo marayo PPAR? xakamaynta (Flint et al., 2016).

Hawsha enzyme HMGCS2 waxa lagu habeeyaa iyada oo loo marayo PTM-yo badan. HMGCS2 serine phosphorylation waxay xoojisay hawlaheeda vitro (Grimsrud et al., 2012). Dhaqdhaqaaqa HMGCS2 waxaa si caadi ah u xannibay succinyl-CoA iyo lysine hadhaaga succinylation (Arias et al., 1995; Hegardt, 1999; Lowe iyo Tubbs, 1985; Quant et al., 1990; Rardin et al., 2013, Red et al. 1975; Thumelin iyo al., 1993). Succinylation of HMGCS2, HMGCL, iyo BDH1 haraaga lysine ee mitochondria hepatic waa bartilmaameedyada NAD + ku tiirsan deacylase sirtuin 5 (SIRT5) (Rardin et al., 2013). Dhaqdhaqaaqa HMGCS2 waxaa sidoo kale kor u qaaday SIRT3 lysine deacetylation, waxaana suurtogal ah in is-dhaafsiga u dhexeeya acetylation iyo succinylation ay nidaamiso dhaqdhaqaaqa HMGCS2 (Rardin et al., 2013; Shimazu et al., 2013). In kasta oo ay awood u leeyihiin PTM-yadan si ay u xakameeyaan HMGCS2 km iyo Vmax, isbedbedelka PTM-yadan weli si taxadar leh looma dejin oo looma xaqiijin darawaliinta makaanikada ee ketogenesis ee vivo.

SCOT waxaa lagu muujiyaa dhammaan unugyada naasleyda ee sida mitochondria, marka laga reebo kuwa hepatocytes. Muhiimadda dhaqdhaqaaqa SCOT iyo ketolysis ayaa lagu muujiyay jiirarka SCOT-KO, kuwaas oo muujiyay halis isku mid ah sababtoo ah hyperketonemic hypoglycemia gudahood 48h ka dib dhalashada (Cotter et al., 2011). Luminta unugyada gaarka ah ee SCOT ee neerfayaasha ama myocytes-ka lafaha lafaha ayaa keena cilladaha dheef-shiid kiimikaadka inta lagu jiro gaajada laakiin maaha mid halis ah (Cotter et al., 2013b). Bini'aadamka, yaraanta SCOT waxay soo bandhigtaa nolosha hore ee ketoacidosis daran, taasoo keenta caajis, matag, iyo miyir beel (Berry et al., 2001; Fukao et al., 2000; Kassovska-Bratinova et al., 1996; Niezen-Koning et al. , 1997; Saudubray iyo al., 1987; Snyderman iyo al., 1998; Tildon iyo Cornblath, 1972). In yar ayaa laga og yahay heerka gacanta ee ku saabsan hidda-wadaha SCOT iyo nidaamiyayaasha hadalka borotiinka. Oxct1 mRNA muujinta iyo borotiinka SCOT iyo nashaadku waa lagu yareeyaa dawladaha ketotic, suurtogalnimada iyada oo loo marayo hababka PPAR-ku-tiirsanaanta (Fenselau iyo Wallis, 1974; Fenselau iyo Wallis, 1976; Grinblat et al., 1986; Okuda et al., 1991; Turko et al ., 2001; Wentz iyo al., 2010). Ketoacidosis-ka macaanka, ismaan-dhaafka u dhexeeya ketogenesis hepatic iyo oksaydhka hepatic hepatic waxa uu noqdaa mid ka sii dara daciifnimada hawlaha SCOT. Xad-dhaafka xad-dhaafka ah ee qaadista gulukooska-madax-bannaan ee insulin-ta (GLUT1 / SLC2A1) ee wadnaha-cardiomyocytes waxay sidoo kale joojisaa muujinta hiddaha Oxct1 waxayna hoos u dhigtaa ketones terminal oksaydhka ee xaalad aan ketotic ahayn (Yan et al., 2009). Beerka, badinta Oxct1 mRNA waxaa lagu xakameynayaa microRNA-122 iyo histone methylation H3K27me3 kuwaas oo muuqda inta lagu jiro kala guurka uurjiifka ilaa xilliga dhalmada (Thorrez et al., 2011). Si kastaba ha ahaatee, xakamaynta muujinta hepatic Oxct1 ee xilliga dhalmada ka dib ayaa ugu horreyntii loo aaneynayaa ka-saarista Oxct1-muujinta hematopoietic progenitors ee beerka, halkii ay lumin lahayd muujinta hore ee Oxct1 ee hepatocytes kala duwan. Dhab ahaantii, muujinta Oxct1 mRNA iyo borotiinka SCOT ee hepatocytes ee kala duwan ayaa aad u hooseeya (Orii et al., 2008).

SCOT sidoo kale waxaa maamula PTM-yada. Enzyme-ku waa hyper-acetylated ee maskaxda SIRT3 KO jiirarka, kaas oo sidoo kale soo bandhigay AcAc ku tiirsanaanta acetyl-CoA (Dittenhafer-Reed et al., 2015). Nitration non-enzymatic ee hadhaaga tyrosine ee SCOT sidoo kale waxay hoos u dhigtaa hawsheeda, kaas oo laga soo sheegay qalbiyada noocyada jiirarka sokorowga ee kala duwan (Marcondes et al., 2001; Turko et al., 2001; Wang et al., 2010a). Taas bedelkeeda, tryptophan hadhaaga nitration waxay kordhisaa waxqabadka SCOT (Br�gre et al., 2010; Rebrin et al., 2007). Hababka molecular ee nitration-gaar ah ee hadhaaga ama de-nitration ee loogu talagalay in lagu beddelo dhaqdhaqaaqa SCOT ayaa laga yaabaa inay jiraan oo u baahan yihiin caddayn.

Khilaafaadka Ketogenesis-ka Heerarka Heerarka

Naasleyda xubinta aasaasiga ah ee ketogenic waa beerka, oo kaliya hepatocytes iyo unugyada epithelial mindhicirka ayaa si weyn u muujinaya soosaarka mitochondrial ee HMGCS2 (Cotter et al., 2013a; Cotter et al., 2014; McGarry iyo Foster, 1980; Robinson iyo Williamson, 1980) . Halsano bakteeriyada anaerobic ee polysaccharides adag waxay soo saartaa butyrate, kaas oo ay nuugaan colonocytes ee naasleyda ee loogu talagalay oxidation terminal ama ketogenesis (Cherbuy et al., 1995), kaas oo door ka ciyaari kara kala soocida colonocyte (Wang et al., 2016). Marka laga reebo unugyada epithelial ee mindhicirka iyo hepatocytes, HMGCS2 waxay ku dhowdahay inay ka maqan yihiin dhammaan unugyada kale ee naasleyda, laakiin rajada ketogenesis-ka ka-baxsan ayaa lagu soo qaaday unugyada burooyinka, astrocytes ee habka dhexe ee neerfayaasha, kelyaha, pancreatic? unugyada, epithelium pigment retinal (RPE), iyo xitaa muruqa lafaha (Adijanto et al., 2014; Avogaro et al., 1992; El Azzouny et al., 2016; Grabacka et al., 2016; Kang et al., 2015); ; Le Foll et al., 2014; Nonaka et al., 2016; Takagi et al., 2016a; Thevenet et al., 2016; Zhang et al., 2011). Ectopic HMGCS2 ayaa lagu arkay unugyo aan lahayn awood ketogenic saafi ah (Cook et al., 2016; Wentz et al., 2010), iyo HMGCS2 waxay soo bandhigaysaa ketogenesis-ka madax-bannaanida nashaadaadka mustaqbalka, oo ay ku jiraan gudaha nukleus unugga (Chen et al. , 2016; Kostiuk iyo al., 2010; Meertens iyo al., 1998).

Unug kasta oo ka baxsan cagaarshow oo oksidheeye jirka ketone waxa kale oo uu awood u leeyahay in uu ururiyo jidhka ketone iyada oo loo marayo hababka madaxbannaan ee HMGCS2 (Jaantus. 2A). Si kastaba ha noqotee, ma jiraan unug ka baxsan cagaarshow kaas oo isku-darka jirka ketone ee joogtada ahi uu ka sarreeyo wareegga wareegga (Cotter et al., 2011; Cotter et al., 2013b; Harrison iyo Long, 1940), taasoo hoosta ka xariiqaysa in ketone meydadka lagu qaado hoos a xooga saarista iyada oo loo marayo habab ku tiirsan MCT1/2. Mid ka mid ah hababka muuqda ee ketogenesis-ka-baxa ee ka baxsan ayaa laga yaabaa inuu dhab ahaantii ka tarjumo daciifnimada ketone oksaydhka. Sharaxaad dheeri ah oo suurtagal ah ayaa ku dhex dhacda gudaha dhismaha ketone jirka. Marka hore, de novo ketogenesis wuxuu ku dhici karaa firfircoonida enzymatic ee thiolase iyo SCOT (Weidemann iyo Krebs, 1969). Marka fiirsashada acetyl-CoA ay sare u kacdo, falcelinta sida caadiga ah masuulka ka ah oksaydhka AcAc waxay u shaqeeyaan jihada kale (GOLDMAN, 1954). Habka labaad waxa uu dhacaa marka ?-oxidation-ka soo jeeda dhex dhexaadiyadu ay ururaan sababtoo ah wareegga wareegga TCA, AcAc-CoA waxaa loo beddelaa l-?OHB-CoA iyada oo loo marayo fal-celin uu sameeyay mitochondrial 3-hydroxyacyl-CoA dehydrogenase, iyo dheeraad ah 3-hydroxybutyryl CoA deacylase ilaa l-?OHB, taas oo aan lagu kala saari karin spectrometry mass spectrometry ama resonance spectroscopy ee physiological enantiomer d-?OHB (Reed and Ozand, 1980). l-?OHB waxay noqon kartaa chromatographically ama enzymatically laga sooci karaa d-?OHB, waxayna ku jirtaa unugyo hepatic ah, laakiin kuma jiraan beerka ama dhiigga (Hsu et al., 2011). Ketogenesis hepatic waxay soo saartaa kaliya d-?OHB, oo kaliya enantiomer kaas oo ah substrate BDH (Ito et al., 1984; Lincoln et al., 1987; Reed iyo Ozand, 1980; Scofield et al., 1982; Scofield et al., 1982). Habka saddexaad ee HMGCS2-madaxa-bannaan ayaa soo saara d-?OHB iyada oo loo marayo catabolism amino acid, gaar ahaan tan leucine iyo lysine. Habka afraad ayaa muuqda oo kaliya sababtoo ah waxaa sabab u ah calaamadaynta farshaxanka oo sidaas awgeed waxaa loogu yeeraa pseudoketogenesis. Dhacdadan waxaa loo aaneynayaa dib-u-celinta SCOT iyo falcelinta thiolase, waxayna sababi kartaa xad-dhaafka isbeddelka jirka ketone sababtoo ah walaxda isotopic ee raadiyaha jirka ee ketone ee unugyada hepatic (Des Rosiers et al., 1990; Fink et al., 1988) . Si kastaba ha ahaatee, pseudoketogenesis ayaa laga yaabaa inay dayacdo xaaladaha badankood (Bailey et al., 1990; Keller et al., 1978). Naqshadeynta (Jaantus. 2A) waxay tusinaysaa hab faa'iido leh oo lagu dabaqayo iyadoo la tixgelinayo kor u kaca heerka unugyada ketones ee joogtada ah.

� Kelyaha ayaa dhawaan helay fiiro gaar ah sida xubin ka iman karta ketogenic. Inta badan gobolada, kelyuhu waa macaamiisha saafiga ah ee jidhka ketone ee beerka ka soo baxa, ka soo saara ama dib u soo celiya jidhka ketone ee dhiigga, iyo kelyaha guud ahaan maaha wax dhaliyaha jidhka ketone saafiga ah ama xoojinta (Robinson iyo Williamson, 1980). Qorayaasha daraasadda qadiimiga ah waxay soo gabagabeeyeen in ketogenesis kelyaha ugu yar ee lagu qiyaaso nidaamka tijaabada macmalka ah uusan ahayn mid jir ahaaneed ku habboon (Weidemann iyo Krebs, 1969). Dhawaan, ketogenesis kelyaha ayaa lagu qiimeeyay noocyada jiirka ee sonkorowga iyo autophagy, laakiin waxay u badan tahay in xubno badan oo ka mid ah isbeddellada dheef-shiid kiimikaadka homeostasis ay beddelaan dheef-shiid kiimikaad ee ketone iyada oo loo marayo xubno badan (Takagi et al., 2016a; Takagi et al., 2016b; Zhang iyo al., 2011). Mid ka mid ah daabacaadadii ugu dambeysay ayaa soo jeedisay ketogenesis kelyaha sidii hab ka hortag ah oo looga hortagayo ischemia-reperfusion dhaawaca kelyaha (Tran et al., 2016). Heerarka xasilloonida buuxda ee ?OHB ee laga soo saaray unugyada kelyaha ee jiirarka ayaa lagu soo warramey ~4�12mM. Si loo tijaabiyo in tani ay tahay mid la awoodi karo, waxaanu qiyaasnay? Heerarka Serum 24C�E), indho-indhayn la jaan qaadaya uruurinta la qiyaasay 100 sano ka hor (Hems iyo Brosnan, 2). Waxaa suurtogal ah in dawladaha ketotic-ka, jidhka ketone ee beerka ka soo baxa ay noqon karaan kuwo difaacaya, laakiin caddaynta ketogenesis kelyaha waxay u baahan tahay caddayn dheeraad ah. Cadaymo adag oo taageeraya ketogenesis-ka kabaxsan ee dhabta ah ayaa lagu soo bandhigay RPE (Adijanto et al., 24). Isbeddelka dheef-shiid kiimikaadka xiisaha leh ayaa la soo jeediyay inuu u oggolaado ketones-ka-soo-baxa RPE-ga inay u qulqulaan unugyada sawir-qaade ama Meller glia, taas oo ka caawin karta dib-u-soo-nooleynta qaybta sare ee sawir-qaadista.

?OHB Dhexdhexaadiyaha Calaamadaha

In kasta oo ay tamar ahaan hodan ku yihiin, jidhka ketone waxa ay ku hawlan yihiin calaamado kicinaya �non-canonical� doorar ku jira homeostasis-ka gacanta (Jaantus. 3) (Newman iyo Verdin, 2014; Rojas-Morales et al., 2016). Tusaale ahaan, ?OHB waxay joojisaa Class I HDACs, taas oo kordhisa histone acetylation oo markaa kicisa muujinta hiddo-wadaha ee xakameynaya cadaadiska oksaydhka (Shimazu et al., 2013). ?OHB lafteedu waa beddelaha unugyada histone ee hadhaaga lysine ee beerka ee jiirarka soonka ama streptozotocin ee ay keento sonkorowga (Xie et al., 2016) Jidhka ketone, walbahaarka oksaydhka, iyo ilaalinta neuroprotection).

?OHB sidoo kale waa saameyn ku yeelashada G-protein-ku-duubayaasha. Iyadoo loo marayo hababka molecular-ka ee aan caddayn, waxay xakameysaa dhaqdhaqaaqa habdhiska dareenka waxayna yareysaa wadarta kharashka tamarta iyo heerka garaaca wadnaha iyada oo la joojinayo calaamadaynta silsiladda dufanka gaaban ee G borotiinka oo ay weheliso receptor 41 (GPR41) (Kimura et al., 2011). Mid ka mid ah saamaynta calaamadaha aadka loo bartay ee ?OHB waxay ku socotaa GPR109A (sidoo kale loo yaqaan HCAR2), xubin ka mid ah qoys hoosaadka hydrocarboxylic acid GPCR oo lagu muujiyey unugyo adipose ah (caddaan iyo bunni) (Tunaru et al., 2003), iyo gudaha unugyada difaaca jirka (Axmed iyo al., 2009). ?OHB waa kan keliya ee loo yaqaan endogenous ligand ee GPR109A reseptor (EC50 ~ 770 �M) ee ay ka shaqeysiisey d-?OHB, l-?OHB, iyo butyrate, laakiin aan AcAc ahayn (Taggart et al., 2005). Xadka ugu sarreeya ee firfircoonida GPR109A waxaa lagu gaaraa u hoggaansanaanta cuntada ketogenic, gaajada, ama inta lagu jiro ketoacidosis, taasoo horseedaysa joojinta lipolysis nudaha adipose. Saamaynta anti-lipolytic ee GPR109A waxay ku socotaa xannibaadda adenylyl cyclase iyo hoos u dhigista cAMP, joojinta hormoonka xasaasiga ah ee triglyceride lipase (Ahmed et al., 2009; Tunaru et al., 2003). Tani waxay abuurtaa wareegga jawaab celinta taban kaas oo ketosis uu ku dhejiyo jebinta isbeddelka ee ketogenesis iyada oo la yareynayo sii deynta asiidhyada dufanka aan la nadiifin ee adipocytes (Ahmed et al., 2009; Taggart et al., 2005), saameyn lagu dheellitiri karo waditaanka naxariista ee kicinaya lipolysis. Niacin (fitamiin B3, nicotinic acid) waa mid awood leh (EC50 ~ 0.1 �M) ligand ee GRP109A, si wax ku ool ah u shaqeeya muddo tobanaan sano ah dyslipidemias (Benyo et al., 2005; Benyo et al., 2006; Fabbrini et al., 2010a Lukasova iyo al., 2011; Tunaru iyo al., 2003). Iyadoo niacin ay xoojiso gaadiidka kolestaroolka ee makrophages-ka oo ay yarayso nabarrada atherosclerotic (Lukasova et al., 2011), saamaynta ?OHB ee nabarrada atherosclerotic ayaan weli la garanayn. In kasta oo GPR109A reseptor uu leeyahay doorar ilaalin ah, iyo xidhiidho xiiso leh ayaa ka dhex jira isticmaalka cuntada ketogenic ee istaroogga iyo cudurrada neurodegenerative (Fu et al., 2015; Rahman et al., 2014), doorka ilaalinta OHB iyada oo loo marayo GPR109A laguma muujin vivo. .

Ugu dambeyntii, ?OHB waxay saameyn kartaa rabitaanka cuntada iyo qanacsanaanta. Falanqaynta maadada ee daraasadaha lagu qiyaasay saamaynta ketogenic iyo cuntooyinka tamarta aadka u hooseeya ayaa lagu soo gabagabeeyay in kaqeybgalayaasha cunaya cuntooyinkan ay muujinayaan satiety sare, marka la barbardhigo cuntooyinka kantaroolka (Gibson et al., 2015). Si kastaba ha ahaatee, sharraxaadda macquulka ah ee saameyntan ayaa ah dheef-shiid kiimikaad dheeraad ah ama hormoonnada hormoonnada kuwaas oo bedeli kara rabitaanka cuntada. Tusaale ahaan, jiirarka lagu ilaaliyo cuntada ketogenic ee jiirka ayaa soo bandhigay qarashka tamarta oo kordhay marka loo eego jiirarka la quudiyo, in kasta oo la qaato kalooriyada la midka ah, iyo wareegga leptin ama hiddo-wadaha peptides ee nidaaminaya habdhaqanka quudinta lama beddelin (Kennedy et al., 2007). Waxaa ka mid ah hababka la soo jeediyay ee soo jeedinaya xakamaynta rabitaanka cuntada ee ?OHB waxaa ku jira calaamadaynta iyo oksaydhka labadaba (Laeger et al., 2010). Tirtiridda gaarka ah ee hepatocyte ee hiddaha laxanka wareegga wareegga (Per2) iyo chromatin immunoprecipitation daraasaadka ayaa shaaca ka qaaday in PER2 ay si toos ah u dhaqaajiso hidda-wadaha Cpt1a, oo ay si dadban u maamusho Hmgcs2, taasoo horseedaysa ketosis daciifka ah ee jiirarka garaaca Per2 (Chavan et al., 2016). Jiirarkan ayaa muujiyay rajada cuntada liidata, kaas oo qayb ahaan uu soo celiyay maamulka OHB. Daraasadaha mustaqbalka ayaa loo baahan doonaa si loo xaqiijiyo habka dhexe ee neerfayaasha sida tooska ah ee bartilmaameedka OHB, iyo haddii ketone oxidation looga baahan yahay saameynta la arkay, ama haddii hab kale oo calaamad ah uu ku lug leeyahay. Baarayaasha kale waxay ku baaqeen suurtagalnimada ketogenesis astrocyte-ka-soo-baxa gudaha ventromedial hypothalamus sida nidaamiyaha qaadashada cuntada, laakiin indha-indheyntan hordhaca ah waxay sidoo kale ka faa'iideysan doontaa qiimeynta hidda-socodka iyo qulqulka ku saleysan (Le Foll et al., 2014). Xidhiidhka ka dhexeeya ketosis iyo nafaqo la'aanta ayaa weli ah xiisaha sababtoo ah gaajada iyo dheriga ayaa ah walxo muhiim ah oo ku jira isku dayga luminta miisaanka.

Isku-dhafka Dheef-shiid kiimikaad ee Jidhka Ketone, Beddelka Turjumaadda Kadib, iyo Fiisiyooloojiyada Unugga

Jidhka Ketone waxay gacan ka geystaan ​​barkadaha la qaybiyay ee acetyl-CoA, dhexdhexaadiye muhiim ah oo soo bandhigaya doorar caan ah oo ku saabsan dheef-shiid kiimikaadka gacanta (Pietrocola et al., 2015). Mid ka mid ah doorka acetyl-CoA waa inuu u adeego sidii substrate for acetylation, wax ka beddelka hiddaha hiddaha enzymatically-catalyzed (Choudhary et al., 2014; Dutta et al., 2016; Fan et al., 2015; Menzies et al., 2016 ). Tiro badan oo borotiinno mitochondrial ah oo firfircoon, kuwaas oo qaar badan oo ka mid ah laga yaabo inay ku dhacaan hababka non-enzymatic, ayaa sidoo kale ka soo baxay daraasadaha borotokoolka xisaabinta (Dittenhafer-Reed et al., 2015; Hebert et al., 2013; Rardin et al., 2013 ; Shimazu iyo al., 2010). Lysine deacetylases waxay isticmaashaa isku-xidhaha zinc (tusaale, nucleocytosolic HDACs) ama NAD+ sidii la-substrate (sirtuins, SIRTs) (Choudhary et al., 2014; Menzies et al., 2016). Acetylproteome-ku wuxuu u adeegaa sida dareemayaasha iyo saamaynta wadarta guud ee barkada gacanta ee acetyl-CoA, sida wax-is-beddelka jireed iyo hidde-sidaha mid kastaa wuxuu keenaa kala duwanaansho caalami ah oo aan enzymatic ahayn ee acetylation (Weinert et al., 2014). Maaddaama dheef-shiid kiimikaad ee intracellular ay u adeegaan sidii modulators of lysine residue acetylation, waxaa muhiim ah in la tixgeliyo doorka ketone meydadka, kuwaas oo badankoodu aad u firfircoon yahay.

?OHB waa beddelka epigenetic iyada oo loo marayo ugu yaraan laba hab. Kordhinta Heerarka OHB ee ay keento soonka, xaddidaadda kalooriga, maamulka tooska ah ama jimicsiga dheeraadka ah waxay kiciyaan xannibaadda HDAC ama firfircoonida histone acetyltransferase (Marosi et al., 2016; Sleiman et al., 2016) ama cadaadiska oksaydhka (Shimazu et al., 2013) . Joojinta OHB ee HDAC3 waxay nidaamin kartaa jir-dhiska dheef-shiid kiimikaadka dhasha (Rando et al., 2016). Si madaxbanaan, ?OHB lafteedu waxay si toos ah u beddeshaa hadhaaga lysine histone (Xie et al., 2016). Soonka dheer, ama ketoacidosis-ka macaanka ee ketoacidosis-ka ee uu keeno steptozotocin ayaa kordhay histone ?-hydroxybutyrylation. Inkasta oo tirada lysine?-hydroxybutyrylation iyo goobaha acetylation ay ahaayeen kuwo is barbar dhig ah, stoichiometrically histone ka weyn -hydroxybutyrylation marka loo eego acetylation ayaa la arkay. Hidde-sideyaasha kala duwan waxaa saameeyay histone lysine?-hydroxybutyrylation, lid ku ah acetylation ama methylation, oo soo jeedinaya hawlo unug oo kala duwan. Haddii ?-hydroxybutyrylation uu yahay mid iskiis ah ama enzymatic lama yaqaan, laakiin waxay ballaarisaa kala duwanaanta hababka iyada oo loo marayo unugyada ketone si firfircoon u saameeya qoraalka.

Dhacdooyinka dib u habeynta unugyada muhiimka ah inta lagu jiro xaddidaadda kalooriyada iyo nafaqo-xumada ayaa laga yaabaa in lagu dhexdhexaadiyo SIRT3-iyo SIRT5-ku-tiirsanaanta mitochondrial deacetylation iyo desuccinylation, siday u kala horreeyaan, nidaaminta borotiinnada ketogenic iyo ketolytic ee heerka tarjumaada ka dib ee beerka iyo unugyada hepatic (Dittenhafer-Reed et al. 2015; Hebert et al., 2013; Rardin iyo al., 2013; Shimazu iyo al., 2010). Inkasta oo isbarbardhigga stoichiometric ee goobaha la haysto uusan si toos ah ula xiriirin isbeddelada qulqulka dheef-shiid kiimikaadka, mitochondrial acetylation waa mid firfircoon waxaana laga yaabaa in ay dhaqaajiso xoojinta acetyl-CoA ama mitochondrial pH, halkii ay ka ahaan lahayd enzymatic acetyltransferases (Wagner iyo Payne, 2013). Taasi SIRT3 iyo SIRT5 waxay habeeyaan hawlaha ketone metabolization enzymes waxay kicisaa su'aasha ah doorka isdhaafsiga ee ketones ee sawirida acetylproteome, succinylproteome, iyo bartilmaameedyada kale ee firfircoon ee gacanta. Runtii, sida kala duwanaanta ketogenesis ay ka tarjumayso uruurinta NAD +, soosaarka ketone iyo badnaanta ayaa nidaamin karta dhaqdhaqaaqa sirtuin, taas oo saameyn ku yeelanaysa wadarta barkadaha acetyl-CoA/succinyl-CoA, acylproteome, iyo sidaas mitochondrial iyo physiology unug. ?-hydroxybutyrylation of enzyme lysine residues waxay ku dari kartaa lakab kale dib u habeynta gacanta. Unugyada hepatic-ka-baxa, oksaydhka jidhka ketone waxa laga yaabaa inuu kiciyo isbeddello isku mid ah oo ku yimaada homeostasis unug. In kasta oo qaybta barkadaha acetyl-CoA si heer sare ah loo habeeyey oo ay isku dubbaridayso muuqaal ballaadhan oo isbeddellada gacanta ah, awoodda jidhka ketone si ay si toos ah u qaabeeyaan labadaba mitochondrial iyo cytoplasmic acetyl-CoA waxay u baahan yihiin sare u qaadis (Chen et al., 2012; Corbet et al., 2016; Pougovkina et al., 2014; Schwer et al., 2009; Wellen iyo Thompson, 2012). Sababtoo ah uruurinta acetyl-CoA si adag ayaa loo habeeyay, iyo acetyl-CoA waa xuubka xuubka, waxaa muhiim ah in la tixgeliyo hababka darawalka ee isku xirka acetyl-CoA homeostasis, oo ay ku jiraan heerarka wax soo saarka iyo oksaydhka terminal ee wareegga TCA, u beddelashada jirka ketone, mitochondrial. efflux iyada oo loo marayo carnitine acetyltransferase (CrAT), ama acetyl-CoA dhoofinta cytosol ka dib markii loo beddelo citrate oo lagu sii daayo ATP citrate lyase (ACLY). Doorarka muhiimka ah ee hababkan dambe ee unugyada acetylproteome iyo homeostasis waxay u baahan yihiin faham isku mid ah oo ku saabsan doorka ketogenesis iyo ketone oxidation (Das et al., 2015; McDonnell et al., 2016; Moussaieff et al., 2015; Overmyer et al., 2015; Seiler et al., 2014; Seiler et al., 2015; Wellen et al., 2009; Wellen iyo Thompson, 2012). Tignoolajiyada isku dhafan ee metabolomics iyo acylproteomics marka la dejinayo moodooyinka hidde ahaan la maareeyay ayaa loo baahan doonaa si loo qeexo yoolalka iyo natiijooyinka.

Jawaabaha Ka-hortagga iyo Ka-hortagga-Bararka ee Jidhka Ketone

Jidhka ketosis iyo ketone waxa ay beddelaan caabuqa iyo shaqada unugyada difaaca, laakiin habab kala duwan iyo xitaa khilaaf ayaa la soo jeediyay. Nafaqo-la'aanta muddada dheer waxay yaraynaysaa bararka (Youm et al., 2015), laakiin ketosis dabadheeraad ah ee nooca 1aad ee sonkorowga waa xaalad pro-bararka (Jain et al., 2002; Kanikarla-Marie iyo Jain, 2015; Kurepa et al., 2012). ). Doorarka calaamadaynta habka-ku-saleysan ee ?OHB ee caabuqa ayaa soo baxaya sababtoo ah unugyo badan oo habka difaaca jirka, oo ay ku jiraan macrophages ama monocytes, ayaa si weyn u muujinaya GPR109A. Iyadoo ?OHB ay bixiso jawaab celin ka hortag ah oo ka hortag ah (Fu et al., 2014; Gambhir et al., 2012; Rahman et al., 2014; Youm et al., 2015), uruurinta sare ee jirka ketone, gaar ahaan AcAc, ayaa laga yaabaa. kicinaya jawaab celin barar ah (Jain et al., 2002; Kanikarla-Marie iyo Jain, 2015; Kurepa et al., 2012).

Doorarka ka-hortagga bararka ee GPR109A ligands ee atherosclerosis, buurnaanta, cudurka mindhicirka bararka, cudurka neerfaha, iyo kansarka ayaa dib loo eegay (Graff et al., 2016). GPR109A muujinta waxaa lagu kordhiyey unugyada RPE ee moodooyinka sonkorowga, bukaannada sokorowga bini'aadamka (Gambhir et al., 2012), iyo microglia inta lagu jiro neurodegeneration (Fu et al., 2014). Saamaynta ka-hortagga bararka ee ?OHB waxaa xoojiyey GPR109A xad-dhaafka ah ee unugyada RPE, oo la tirtiro xannibaadda dawooyinka ama garaaca hidda-socodka ee GPR109A (Gambhir et al., 2012). ?OHB iyo nicotinic acid exogenous (Taggart et al., 2005), labaduba waxay bixiyaan saamaynta anti-bararka ee TNF? ama bararka ay keentay LPS iyadoo hoos loo dhigayo heerarka borotiinka pro-bararka (iNOS, COX-2), ama cytokines qarsoon (TNF?, IL-1?, IL-6, CCL2/MCP-1), qayb ahaan iyada oo la joojinayo NF -? Turjumida B (Fu et al., 2014; Gambhir iyo al., 2012). ?OHB waxay yaraynaysaa diiqada ER iyo NLRP3 barar, iyada oo dhaqaajisa jawaabta diiqada oksidheer (Bae et al., 2016; Youm et al., 2015). Si kastaba ha ahaatee, caabuqa neurodegenerative, GPR109A-ku-tiirsanaanta wax soo saarka (Rahman et al., 38). Waa arrin xiiso leh in macrophage GPR2014A looga baahan yahay inuu sameeyo saameyn neuroprotective ee qaabka istaroogga ischemic (Rahman et al., 1), laakiin awoodda OHB si loo xakameeyo caabuqa NLRP2 ee macrophages dhuuxa lafaha waa GPR2014A madaxbannaan (Youm et al. ., 109). Inkasta oo daraasadaha intooda badani ay ku xidhaan ?OHB saamaynta anti-bararka, ?OHB waxay noqon kartaa pro-bararka iyo kordhinta calaamadaha lipid peroxidation ee hepatocytes kubka (Shi et al., 2014). Saamaynta ka-hortagga-bararka ee OHB waxay sidaas ku xirnaan kartaa nooca unugga, ?fiirsashada OHB, muddada soo-gaadhista, iyo joogitaanka ama maqnaanshaha wada-hawlgalayaasha.

Si ka duwan ?OHB, AcAc waxa laga yaabaa inay dhaqaajiso calaamadaynta ka hortagga caabuqa. AcAc oo sare u kacday, gaar ahaan gulukoos-kooxeed sare, waxay xoojisaa dhaawaca unugga endothelial iyada oo loo marayo habka NADPH oxidase / oksijiinta ku tiirsanaanta (Kanikarla-Marie iyo Jain, 2015). Heerarka sare ee AcAc ee xuddunta hooyooyinka sonkorowga qaba ayaa lala xiriiriyay heerka oksaydhka borotiinka sare iyo xoojinta MCP-1 (Kurepa et al., 2012). AcAc sare ee bukaanka sokorowga ayaa lala xiriiriyay TNF? muujinta (Jain et al., 2002), iyo AcAc, laakiin maaha?OHB, TNF oo la kiciyay?, MCP-1 muujinta, ururinta ROS, iyo hoos u dhaca heerka CAMP ee unugyada monocyte ee U937 (Jain et al., 2002; Kurepa et al). ., 2012).

Calaamadaha calaamadaha ku-tiirsanaanta jirka ee ketone waxaa badanaa lagu kiciyaa kaliya ketone jirka oo sarreeya (> 5 mM), iyo xaaladda daraasado badan oo isku xira ketones-ka saameynaha pro-ama anti-bararka, iyada oo loo marayo habab aan caddayn. Intaa waxaa dheer, sababtoo ah saamaynta is burinaya ee OHB ka soo horjeeda AcAc ee caabuqa, iyo awoodda AcAc /? OHB ratio si ay u saameeyaan mitochondrial redox iman kara, tijaabooyinka ugu fiican ee lagu qiimeeyo doorka ketone meydadka ee phenotypes gacanta barbar barbar saamaynta AcAc iyo ? OHB ee saamiyo kala duwan, iyo kala duwanaansho isu-ururin [tusaale, (Saito et al., 2016)]. Ugu dambeyntii, AcAc waxaa loo iibsan karaa ganacsi ahaan kaliya sida lithium milix ah ama sida ethyl ester oo u baahan hydrolysis salka ka hor isticmaalka. Lithium cation si madax-bannaan u kicisa calaamadaha gudbinta calaamadaha (Manji et al., 1995), iyo AcAc anion waa labile. Ugu dambeyntii, daraasadaha la isticmaalayo jinsiyadda d/l-?OHB waa la jahawareerin karaa, maadaama kaliya d-?OHB stereoisomer lagu oksidiin karo AcAc, laakiin d-?OHB iyo l-?OHB mid kastaa waxay calaamadeyn karaan iyada oo loo marayo GPR109A, waxay joojin karaan NLRP3 barar, oo u adeega sida substrates lipogenic.

Jidhka Ketone, Cadaadiska Oxidative, iyo Ilaalinta Neuro

Cadaadiska Oxidative waxaa sida caadiga ah lagu qeexaa sida xaalad ROS lagu soo bandhigo si xad dhaaf ah, taasoo ay ugu wacan tahay wax-soo-saarka xad-dhaafka ah iyo/ama baabi'inta daciifka ah. Antioxidant iyo cadaadiska oksaydhiyaha ee yaraynta doorka ketone ayaa si weyn loogu sharraxay labadaba gudaha vitro iyo gudaha, gaar ahaan macnaha guud ee ilaalinta neuroprotection. Maaddaama neurons-yada intooda badani aysan si wax ku ool ah u dhalin fosfooraska tamarta sare leh ee acids dufanka leh, laakiin waxay oxidize jirka ketone marka karbohaydraytyadu ay gabaabsi yihiin, saamaynta neuroprotective ee jirka ketone ayaa si gaar ah muhiim u ah (Cahill GF Jr, 2006; Edmond et al., 1987; Yang iyo al., 1987). Noocyada cadaadiska oksaydhka, soo-saarka BDH1 iyo xakamaynta SCOT waxay soo jeedinayaan in dheef-shiid kiimikaadka jirka ee ketone dib loo habeyn karo si loo joogteeyo calaamadaha unugyada kala duwan, awoodda dib-u-celinta, ama shuruudaha dheef-shiid kiimikaadka (Nagao et al., 2016; Tieu et al., 2003).

Jidhka Ketone wuxuu hoos u dhigaa darajooyinka dhaawaca gacanta, dhaawaca, dhimashada iyo apoptosis hoose ee neurons iyo cardiomyocytes (Haces et al., 2008; Maalouf et al., 2007; Nagao et al., 2016; Tieu et al., 2003). Hababka la soo jeediyay waa kala duwan yihiin oo aan had iyo jeer toos ahayn xiriir la leh diiradda. Xajmiga millimolar-yar ee (d ama l) -? OHB scavenge ROS (hydroxyl anion), halka AcAc ay soo saartay noocyo badan oo ROS ah, laakiin kaliya ee ka sarreeya qiyaasta jir ahaaneed (IC50 20�67 mM) (Haces et al., 2008) . Taa beddelkeeda, saameyn faa'iido leh oo ku saabsan awoodda dib-u-habaynta silsiladda gaadiidka elektaroonigga ah waa farsamo caadi ahaan ku xiran d-?OHB. Iyadoo dhammaan saddexda ketone ee jirka ah (d/l-?OHB iyo AcAc) ay hoos u dhigeen dhimashada unugyada neerfaha iyo ururinta ROS ee ay keentay xakameynta kiimikada ee glycolysis, kaliya d-?OHB iyo AcAc ayaa ka hortagay hoos u dhaca ATP ee neuronal. Taa beddelkeeda, qaabka hypoglycemic ee vivo model, (d ama l) -? OHB, laakiin ma aha AcAc ka hortagtay lipid peroxidation hippocampal (Haces et al., 2008; Maalouf et al., 2007; Marosi et al., 2016; Murphy, 2009 Tieu iyo al., 2003). Daraasadaha vivo ee jiirarka ayaa quudiyay cunto ketogenic ah (87% dufanka kcal iyo 13% borotiinka) waxay muujiyeen kala duwanaanshaha neuroanatomical ee awoodda antioxidant (Ziegler et al., 2003), halkaasoo isbeddelada ugu qoto dheer lagu arkay hippocampus, iyadoo la kordhinayo glutathione peroxidase iyo wadarta guud. awoodaha antioxidant.

Cunto ketogenic ah, ketone esters (sidoo kale eeg isticmaalka daaweynta ee cuntada ketogenic iyo jidhka ketone dibadda), ama? Cudurka Parkinson (Tieu et al., 2014); suuxdinta sunta ogsijiinta habdhiska dareenka dhexe (D'Agostino et al., 2003); suuxdin (Yum et al., 2013); mitochondrial encephalomyopathy, lactic acidosis iyo istaroogga-sida (MELAS) dhacdooyinka cilladaha (Frey et al., 2015) iyo cudurka Alzheimers (Cunnane iyo Crawford, 2016; Yin et al., 2003). Taa bedelkeeda, warbixin dhowaan ayaa muujisay caddaynta taariikhiga ah ee horumarka neurodegenerative ee cuntada ketogenic ee qaabka jiirka transgenic ee dayactirka mitochondrial DNA ee aan caadiga ahayn, inkastoo kororka biogenesis mitochondrial iyo saxeexyada antioxidant (Lauritzen et al., 2016). Warbixinno kale oo iska soo horjeeda waxay soo jeedinayaan in soo-gaadhista isku-ururinta jidhka ketone ee sarreeya ay keento cadaadiska oksaydhka. Qiyaasta sare ee OHB ama AcAc waxay keentay dheecaanka nitric oxide, lipid peroxidation, muujinta hoos u dhaca SOD, glutathione peroxidase iyo catalase ee hepatocytes kubka, halka hepatocytes ee jiirka ku jira dariiqa MAPK loo nisbeeyay AcAc laakiin maaha?OHB (Abdelmegeed et al., 2016). ; Shii iyo al., 2004; Shii iyo al., 2014).

Isku soo wada duuboo, warbixinada intooda badani waxay ku xidhaan ?OHB inay hoos u dhigto cadaadiska oksaydhiyaha, maadaama maamulkeedu uu joojinayo wax soo saarka ROS/superoxide, ka hortagayo peroxidation lipid iyo oksaydhka borotiinka, waxay kordhisaa heerarka borotiinka antioxidant, waxayna wanaajisaa neefsiga mitochondrial iyo wax soo saarka ATP (Abdelmegeed et al., 2004; Haces et al., 2008; Jain et al., 1998; Jain et al., 2002; Kanikarla-Marie iyo Jain, 2015; Maalouf et al., 2007; Maalouf iyo Rho, 2008; Marosi et al., 2016; Tieu iyo al., 2003; Yin iyo al., 2016; Ziegler iyo al., 2003). Iyadoo AcAc ay si toos ah ula xiriirtay OHB oo ay la socoto kicinta cadaadiska oksaydhiyaha, saameynahaan had iyo jeer si fudud uma kala soocaan jawaabaha pro-bararka ee mustaqbalka (Jain et al., 2002; Kanikarla-Marie iyo Jain, 2015; Kanikarla-Marie iyo Jain, 2016). Waxaa intaa dheer, waxaa muhiim ah in la tixgeliyo in faa'iidada antioxidative ee muuqata ee ay bixiso cuntooyinka ketogenic pleiotropic laga yaabo in aan lagu beddelin ketone laftooda, iyo ilaalinta neuroprotection ee ay bixiso jirka ketone lagama yaabo in gebi ahaanba loo aaneeyo cadaadiska oksaydhka. Tusaale ahaan inta lagu jiro gulukoos-yarida, oo ah qaabka gulukooska gulukooska ee neerfayaasha kortikal, ?OHB waxay kicisay qulqulka autophagic waxayna ka hortagtay isku-ururinta autophagosome, taas oo lala xiriiriyay hoos u dhaca dhimashada neuronal (Camberos-Luna et al., 2016). d-?OHB waxay sidoo kale soo saartaa borotiinnada antioxidant-ka FOXO3a, SOD, MnSOD, iyo catalase, iyada oo loo marayo xannibaadda HDAC (Nagao et al., 2016; Shimazu et al., 2013).

Cudurka Beerka Dufan ee Aan Khamriga ahayn (NAFLD) iyo Dheef-shiid kiimikaadka Jidhka Ketone

Cayilka-la-xiran ee NAFLD iyo steatohepatitis-ka aan khamriga ahayn (NASH) ayaa ah sababaha ugu badan ee cudurrada beerka ee dalalka reer galbeedka (Rinella iyo Sanyal, 2016), iyo NASH-ku-dhacey beerka ayaa ah mid ka mid ah sababaha ugu badan ee beerka beerka. Iyadoo kaydinta xad-dhaafka ah ee triacylglycerol ee hepatocytes> 5% miisaanka beerka (NAFL) oo keliya ma keenayso shaqada beerka oo xumaata, horumarka NAFLD ee bini'aadamku wuxuu la xidhiidha caabbinta insulin-ta habaysan iyo khatarta sii kordheysa ee nooca 2 ee sonkorowga, waxaana laga yaabaa inay gacan ka geysato pathogenesis cudurrada wadnaha iyo xididdada dhiigga iyo cudurrada kelyaha ee joogtada ah (Fabbrini et al., 2009; Targher et al., 2010; Targher iyo Byrne, 2013). Hababka cudur-sidaha ee NAFLD iyo NASH si aan dhammaystirnayn looma fahmin laakiin waxaa ka mid ah cilladaha dheef-shiid kiimikaadka hepatocyte, hepatocyte autophagy iyo endoplasmic reticulum stress, shaqada unugyada difaaca ee hepatic, caabuq unugyada adipose, iyo dhexdhexaadiyeyaasha caabuqa nidaamka (Fabbrini et al., 2009; Masuoka iyo Chalasani, 2013). ; Targher iyo al., 2010; Yang iyo al., 2010). Dhibaatooyinka karbohaydraytyada, dufanka, iyo dheef-shiid kiimikaadka amino acid waxay ku dhacaan waxayna gacan ka geystaan ​​cayilka, sonkorowga, iyo NAFLD ee bini'aadamka iyo noolaha moodada ah [dib u eegis lagu sameeyay (Farese et al., 2012; Lin iyo Accili, 2011; Newgard, 2012; Samuel iyo Shulman, 2012; Qorraxda iyo Lazar, 2013)]. Iyadoo cilladaha hepatocyte-ka ee dheef-shiid kiimikaadka cytoplasmic lipid si caadi ah lagu arkay NAFLD (Fabbrini et al., 2010b), doorka dheef-shiid kiimikaadka mitochondrial, kaas oo xukuma qashinka oksijiinta ee dufanka ayaa ah mid aad u cad in NAFLD pathogenesis. Dhibaatooyinka aan caadiga ahayn ee dheef-shiid kiimikaadka mitochondrial ayaa ku dhaca oo gacan ka geysta NAFLD / NASH pathogenesis (Hyotylainen et al., 2016; Serviddio et al., 2011; Serviddio et al., 2008; Wei et al., 2008). Waxaa jira guud (Felig et al., 1974; Iozzo et al., 2010; Koliaki et al., 2015; Satapati et al., 2015; Satapati et al., 2012; Sunny et al., 2011) laakiin aan labis ahayn ( Koliaki iyo Roden, 2013; Perry et al., 2016; Rector et al., 2010) waxay isku raaceen in, ka hor horumarinta NASH, cagaarshow mitochondrial hepatic, iyo gaar ahaan oxidation dufan, ayaa lagu kordhiyey cayilka, iska caabbinta insulin nidaamsan. iyo NAFLD. Waxay u badan tahay in marka NAFLD uu sii socdo, awoodda oksijiinta heterogenity, xitaa ka mid ah mitochondria shakhsi ahaaneed, ayaa soo baxa, iyo ugu dambeyntii shaqada oksaydhisku waxay noqotaa mid daciif ah (Koliaki et al., 2015; Rector et al., 2010; Satapati et al., 2008; Satapati et al. ., 2012).

Ketogenesis waxaa badanaa loo isticmaalaa wakiil ahaan oksidation dufanka beerka. Naafanimada ketogenesis waxay soo baxdaa iyadoo NAFLD ay ku sii socoto moodooyinka xayawaanka, waxayna u badan tahay in bini'aadamka. Iyadoo loo marayo habab aan dhammaystirnayn, hyperinsulinemia waxay xakameysaa ketogenesis, oo laga yaabo inay gacan ka geysato hypoketonemia marka la barbardhigo kontaroolada caatada ah (Bergman et al., 2007; Bickerton et al., 2008; Satapati et al., 2012; Soeters et al., 2009; Sunny , 2011; ku xigeenka iyo al., 2005). Si kastaba ha ahaatee, awoodda wareegga wareegga jirka ketone si loo saadaaliyo NAFLD waa muran (M�nnist� et al., 2015; Sanyal et al., 2001). Hababka spectroscopic resonance magnetic quantitative spectroscopic ee moodooyinka xayawaanka ayaa muujiyay kororka heerka isbedbedelka ketone oo leh iska caabbinta insulin dhexdhexaad ah, laakiin heerarka hoos u dhaca ayaa ka muuqday iska caabin insulin oo aad u daran (Satapati et al., 2012; Sunny et al., 2010). Dadka cayilan ee leh beerka dufanka leh, heerka ketogenic waa caadi (Bickerton et al., 2008; Sunny et al., 2011), oo markaa, heerarka ketogenesis waa la dhimay marka loo eego kororka asiidhka dufanka leh ee hepatocytes. Sidaa awgeed, ?-oxidation-derived acetyl-CoA waxaa laga yaabaa in lagu jiheeyo oksaydhka terminal ee wareegga TCA, kordhinta oksaydhka terminal, phosphoenolpyruvate-driven gluconeogenesis iyada oo loo marayo anaplerosis/cataplerosis, iyo walbahaarka oksaydhka. Acetyl-CoA sidoo kale waxaa suurtogal ah in laga dhoofiyo mitochondria sida citrate, substrate horudhac ah oo loogu talagalay lipogenesis (Jaantus. 4) (Satapati et al., 2015; Satapati et al., 2012; Solinas et al., 2015). Iyadoo ketogenesis uu noqdo mid ka jawaab celinaya insulin ama soonka oo leh cayil dabadheeraad ah (Satapati et al., 2012), hababka hoose iyo cawaaqibka hoose ee tan ayaa weli ah mid aan dhammaystirnayn. Caddaynta dhawaa waxay muujinaysaa in mTORC1 ay xakamayso ketogenesis qaab laga yaabo inay hoos u dhigto calaamadaha insulinta (Kucejova et al., 2016), taas oo la socota indho-indhaynta in mTORC1 ay joojiso PPAR-dhexdhexaadinta Hmgcs2 (Sengupta et al., 2010) sidoo kale eeg Xeerka HMGCS2 iyo SCOT/OXCT1).

Indho-indheynta hordhaca ah ee kooxdayadu waxay soo jeedinayaan cawaaqib xumada beerka ee ku filnaansho la'aanta ketogenic (Cotter et al., 2014). Si loo tijaabiyo mala-awaalka daciifiyay ketogenesis, xitaa karbohaydrayt-buuxsan oo sidaas darteed gobolada aan-ketogenic-ka ahayn, waxay gacan ka geysataa dheef-shiid kiimikaadka gulukooska ee aan caadiga ahayn waxayna kicisaa steatohepatitis, waxaan soo saarnay moodal jiirka ah oo ku filnaan la'aanta ketogenic ee calaamadsan maamulka oligonucleotides antisense (ASO) ee lala beegsaday Hmgcs2. Luminta HMGCS2 ee jiirarka caadiga ah ee dufanku ku yar yahay ee lagu quudiyo qaangaarka ayaa sababay hyperglycemia khafiif ah iyo wax soo saarka si muuqata u kordhay boqolaal dheef-shiid kiimikaad cagaarshow, kaas oo si adag u soo jeediyay firfircoonida lipogenesis. Quudinta dufanka badan ee jiirarka leh ketogenesis aan ku filnayn ayaa keentay dhaawac ballaaran oo cagaarshow iyo barar. Natiijooyinkani waxay taageeraan mala-awaalka dhexe ee ah (i) ketogenesis maaha dariiq qulqulaya oo aan caadi ahayn, laakiin waa noode firfircoon oo ku jira cagaarshow iyo isku-dhafka jireed ee homeostasis, iyo (ii) kordhinta ketogenic miyir-qabka ah si loo yareeyo NAFLD / NASH iyo dheef-shiid kiimikaadka beerka ee khalkhalka ayaa u qalma sahaminta. .

Sidee bay ketogenesis liidata wax ugu biirin kartaa dhaawaca beerka iyo gulukooska homeostasis oo beddelmay? Tixgelinta koowaad waa haddii dembiilaha uu yahay yaraanta qulqulka ketogenic, ama ketones laftooda. Warbixin dhawaan la soo saaray ayaa soo jeedinaysa in jidhka ketone laga yaabo in uu yareeyo dhaawaca beerka ee cadaadiska oksaydhative-ku keeno iyada oo laga jawaabayo n-3 polyunsaturated fatty acids (Pawlak et al., 2015). Xusuusnow in ay sabab u tahay muujinta SCOT ee hepatocytes, jidhka ketone maaha mid oksaydhaysan, laakiin waxay gacan ka geysan karaan lipogenesis, oo waxay u adeegi karaan doorar tilmaame oo kala duwan oo ka madax bannaan oksaydhkooda (sidoo kale eeg heerka dheef-shiid kiimikaad ee aan oksaydhka ahayn ee jidhka ketone iyo ?OHB sida dhexdhexaadiye tilmaame). Waxa kale oo suurtogal ah in unugyada ketone hepatocyte-ka-soo-baxa ay u adeegi karaan calaamad iyo/ama dheef-shiid kiimikaad ee noocyada unugyada deriska ah ee ku dhex jira acinus cagaarshow, oo ay ku jiraan unugyada stellate iyo macrophages unug Kupffer. In kasta oo suugaanta xaddidan ee la heli karo ay soo jeedinayso in makrophages-ku aanay awood u lahayn inay oksijiyeen jidhka ketone, tan waxa kaliya lagu cabbiray iyadoo la adeegsanayo hababka qadiimiga ah, oo keliya makrofajiyada peritoneal (Newsholme et al., 1986; Newsholme et al., 1987), taasoo muujinaysa in dib u Qiimaynta ayaa ku haboon marka la eego muujinta SCOT ee badan ee makrophages-ka dhuuxa lafta (Youm et al., 2015).

Hepatocyte ketogenic flux wuxuu kaloo noqon karaa cytoprotective. Iyadoo hababka salutary laga yaabaa in aanay ku xidhan ketogenesis per se, cuntooyinka ketogenic carbohydrate hooseeya ayaa lala xiriiriyay hagaajinta NAFLD (Browning et al., 2011; Foster et al., 2010; Kani et al., 2014; Schugar iyo Crawford, 2012) . Aragtideenna waxay muujinayaan in ketogenesis hepatocyte laga yaabo inay dib u soo celiso oo ay nidaamiso wareegga wareegga TCA, qulqulka anaplerotic, gluconeogenesis-ka-soo-saarka fosfoenolpyruvate (Cotter et al., 2014), iyo xitaa isbeddelka glycogen. Naafanimada Ketogenic waxay toosisaa acetyl-CoA si ay u kordhiso qulqulka TCA, kaas oo beerka ku jira ayaa lala xiriiriyay korodhka dhaawaca dhexdhexaadiyaha ROS (Satapati et al., 2015; Satapati et al., 2012); xoog u leexinta kaarboonka oo loo rogo de novo noocyada dufanka samaysmay ee caddayn kara cytotoxic; waxayna ka hortagtaa NADH dib-u-oxidation NAD + (Cotter et al., 2014) (Jaantus. 4). Isku soo wada duuboo, tijaabooyinka mustaqbalka ayaa loo baahan yahay si wax looga qabto hababka ay ku filnaan la'aanta ketogenic ee qaraabo ay noqon karto mid aan wanaagsanayn, gacan ka geysata hyperglycemia, kicinta steatohepatitis, iyo haddii hababkani ay ku shaqeeyaan NAFLD/NASH bini'aadamka. Sida caddaynta cudurrada faafa ay soo jeedinayso ketogenesis daciifka ah inta lagu jiro horumarka steatohepatitis (Embade et al., 2016; Marinou et al., 2011; M�nnist� et al., 2015; Pramfalk et al., 2015; Safaei et al., 2016) daawaynta kordhinaysa ketogenesis hepatic waxay caddayn kartaa salutary (Degirolamo et al., 2016; Honda et al., 2016).

Jidhka Ketone iyo Wadna xanuunka (HF)

Iyada oo heerka dheef-shiid kiimikaadka ka sarreeya 400 kcal/kg/maalintii, iyo isbeddelka 6 kg ATP/maalintii, wadnuhu waa xubinta ugu badan ee kharashaadka tamarta iyo baahida oksaydhka (Ashrafian et al., 35; Wang et al., 2007b). Inta badan wareegga tamarta myocardial waxay ku dhex nool yihiin mitochondria, 2010% sahaydan waxay ka timid FAO. Wadnaha waa wax walba oo isbedelaya xaaladaha caadiga ah, laakiin wadnaha dib-u-qaabaynta pathologically (tusaale, hypertension ama wadnaxanuun myocardial) iyo wadnaha sonkorowga mid kastaa wuxuu noqdaa mid dheef-shiid kiimikaad ah (Balasse iyo Fery, 70; BING, 1989; Fukao et al., 1954). Lopaschuk iyo al., 2004; Taegtmeyer iyo al., 2010; Taegtmeyer iyo al., 1980; Young et al., 2002). Runtii, cilladaha hidde ahaan loo qorsheeyay ee dheef-shiid kiimikaadka wadnaha wadnaha ee moodooyinka jiirka waxay kiciyaan wadnaha wadnaha (Carley et al., 2002; Neubauer, 2014). Marka la eego xaaladaha jireed, wadnaha caadiga ah wuxuu oxidize jirka ketone marka loo eego dhalashadooda, iyadoo kharashka ku baxaya aashitada dufanka iyo gulukooska oxidation, iyo myocardium waa macaamiisha jidhka ugu sarreeya ee ketone halkii cuf (BING, 2007; Crawford et al., 1954; GARLAND et al). ., 2009; Hasselbaink iyo al., 1962; Jeffrey et al., 2003; Pelletier et al., 1995; Tardif et al., 2007; Yan et al., 2001). Marka la barbardhigo oksaydhka aashitada dufanka leh, jidhka ketone ayaa aad waxtar u leh, oo soo saara tamar badan oo loo heli karo isku-darka ATP halkii molecule ee ogsijiinta la maalgeliyay (Kashiwaya et al., 2009; Sato et al., 2010; Veech, 1995) . oksaydhka jirka Ketone waxa kale oo uu keenaa tamar ka awood badan FAO, ilaalinta ubiquinone oxidized, taas oo kor u qaadaysa dhererka redox ee silsiladda gaadiidka elektaroonigga ah oo ka dhigaysa tamar badan oo la heli karo si loo dardargeliyo ATP (Sato et al., 2004; Veech, 1995). Oxidation-ka jirka ketone waxa kale oo laga yaabaa in uu yareeyo wax soo saarka ROS, oo sidaas awgeed diiqada oksaydhka (Veech, 2004).

Faragelinta hordhaca ah iyo daraasaadka indho-indheynta ayaa tilmaamaya doorka saliimka ah ee jirka ketone ee wadnaha ee suurtagalka ah. Marka la eego xaaladda tijaabada ah ee ischemia/reperfusion macnaha guud, jidhka ketone waxa uu keenay saamayn ka hortag ah oo wadnaha ah (Al-Zaid et al., 2007; Wang et al., 2008), laga yaabaa inay sabab u tahay kororka tirada mitochondrial ee wadnaha ama kor u qaadida nidaaminta fosfooraska oksaydhka muhiimka ah. dhexdhexaadiyeyaasha (Snorek et al., 2012; Zou et al., 2002). Daraasadihii ugu dambeeyay waxay muujinayaan in ka faa'iidaysiga jidhka ketone uu kordhay qalbiyada jilicsan ee jiirarka (Aubert et al., 2016) iyo bini'aadamka (Bedi et al., 2016), taageeraya indha-indheyn hore ee bini'aadamka (BING, 1954; Fukao et al., 2000; Janardhan et al., 2011; Longo et al., 2004; Rudolph iyo Schinz, 1973; Tildon iyo Cornblath, 1972). Isku-darka jirka ketone ee wareega ayaa lagu kordhiyaa bukaannada wadne xanuunka wadnaha, marka loo eego saamiga tooska ah ee buuxinta cadaadiska, indho-indheynta habka iyo muhiimada aan la garanayn (Kupari et al., 1995; Lommi et al., 1996; Lommi et al., 1997; Neely et al. ., 1972), laakiin jiirarka leh yaraanta SCOT ee xulashada wadnaha ee wadnaha waxay muujinayaan dib-u-habaynta ventricular pathological ee degdega ah iyo saxeexyada ROS ee ka jawaabaya dhaawaca culeyska cadaadiska qaliinka (Schugar et al., 2014).

Indho-indheyntii ugu dambeysay ee daaweynta sonkorowga ayaa shaaca ka qaaday xiriirka suurtagalka ah ee ka dhexeeya dheef-shiid kiimikaadka ketone myocardial iyo dib-u-qaabaynta ventricular pathological (Jaantus. 5). Joojinta kalyaha proximal tubular sodium/glucose co-transporter 2 (SGLT2i) waxay kordhisaa wareegga jirka ketone ee bini'aadamka (Ferranni et al., 2016a; Inagaki et al., 2015) iyo jiirarka (Suzuki et al., 2014) ketogenesis hepatic (Ferrannini et al., 2014; Ferrannini et al., 2016a; Katz iyo Leiter, 2015; Mudaliar et al., 2015). Si la yaab leh, ugu yaraan mid ka mid ah wakiiladan ayaa hoos u dhigay isbitaalka HF (tusaale, sida ay shaaca ka qaaday tijaabada OUTCOME EMPA-REG), iyo horumarinta dhimashada wadnaha iyo xididdada dhiigga (Fitchett et al., 2016; Sonesson et al., 2016; Wu et al., 2016a Zinman iyo al., 2015). Iyadoo hababka darawalka ee ka dambeeya natiijooyinka HF ee faa'iidada leh ee ku xiran SGLT2i ay yihiin kuwo si firfircoon looga doodayo, faa'iidada badbaadada waxay u badan tahay in ay ka mid yihiin ketosis laakiin sidoo kale saameynta salutary ee miisaanka, cadaadiska dhiigga, gulukooska iyo heerarka uric acid, qallafsanaanta halbowlaha, nidaamka dareenka dareenka, osmotic diuresis / hoos u dhaca mugga balaasmaha, iyo korodhka hematocrit (Raz iyo Cahn, 2016; Vallon iyo Thomson, 2016). Isku soo wada duuboo, fikradda ah in si tartiib tartiib ah u kordheysa ketonemia midkoodna bukaannada HF, ama kuwa halista sare ugu jira inay horumariyaan HF, ayaa weli ah mid muran dhaliyay laakiin waxay ku socotaa baaritaan firfircoon oo ku saabsan daraasadaha hore ee caafimaadka iyo kiliinikada (Ferranni et al., 2016b; Kolwicz et al., 2016; Lopaschuk iyo Verma, 2016; Mudaliar et al., 2016; Taegtmeyer, 2016).

Jidhka Ketone ee Biology-ga Kansarka

Xidhiidhada ka dhexeeya jidhka ketone iyo kansarku si degdeg ah ayay u soo baxayaan, laakiin daraasadaha labada nooc ee xayawaanka iyo bini'aadamku waxay keeneen gunaanadyo kala duwan. Sababtoo ah dheef-shiid kiimikaadka ketone waa firfircooni iyo xaalad nafaqo oo jawaab celin ah, waxay soo jiidaneysaa in la sii wado xiriirka bayoolojiga ee kansarka sababtoo ah suurtagalnimada daaweynta nafaqada ee saxda ah. Unugyada kansarku waxay maraan dib-u-habeeynta dheef-shiid kiimikaadka si loo ilaaliyo kororka unugyada degdega ah iyo koritaanka (DeNicola iyo Cantley, 2015; Pavlova iyo Thompson, 2016). Saamaynta Warburg ee qadiimiga ah ee dheef-shiid kiimikaadka unugyada kansarka ayaa ka soo baxa doorka ugu sarreeya ee glycolysis iyo halsano lactic acid si loogu wareejiyo tamarta loona magdhabo ku tiirsanaanta hoose ee fosforyaalka oksaydhka iyo neefsiga mitochondrial xaddidan (De Feyter et al., 2016; Grabacka et al., 2016; Kang et al., 2015; Poff et al., 2014; Shukla et al., 2014). Kaarboonka gulukooska waxaa ugu horreyn lagu hagayaa glycolysis, dariiqa fosfooraska ee pentose, iyo lipogenesis, kuwaas oo si wada jir ah u bixiya dhexdhexaadiyeyaasha lagama maarmaanka u ah ballaarinta biomass buro (Grabacka et al., 2016; Shukla et al., 2014; Yoshii et al., 2015). La qabsiga unugyada kansarka ee gulukoos-la'aanta waxay ku dhacdaa iyada oo loo marayo awoodda looga faa'iidaysto ilaha shidaalka kale, oo ay ku jiraan acetate, glutamine, iyo aspartate (Jaworski et al., 2016; Sullivan et al., 2015). Tusaale ahaan, helitaanka xaddidan ee pyruvate waxay muujinaysaa awoodda unugyada kansarka si ay ugu beddelaan glutamine-ka acetyl-CoA by carboxylation, ilaalinta labadaba baahida tamarta iyo anabolic (Yang et al., 2014). La qabsiga xiisaha leh ee unugyada kansarka waa isticmaalka acetate sida shidaalka (Comerford et al., 2014; Jaworski et al., 2016; Mashimo et al., 2014; Wright iyo Simone, 2016; Yoshii et al., 2015). Acetate sidoo kale waa substrate for lipogenesis, taas oo muhiim u ah kororka unugyada burooyinka, iyo helitaanka marin-biyoodkan lipogenic waxay la xiriirtaa badbaadada bukaanka gaaban iyo culeyska weyn ee buro (Comerford et al., 2014; Mashimo et al., 2014; Yoshii et al. ., 2015).

Unugyada aan kansarka ahayn waxay si fudud isha tamarta uga beddelaan gulukoosta una beddelaan jidhka ketone inta lagu jiro gulukoos-la'aanta. Balaastigani wuxuu noqon karaa mid aad u kala duwan oo ka dhex jira noocyada unugyada kansarka, laakiin gudaha vivo burooyinka maskaxda ee la galiyay oxidized [2,4-13C2] -? OHB heer la mid ah sida unugyada maskaxda ku wareegsan (De Feyter et al., 2016). �Saamaynta Warburg ee rogaal celiska ah ama laba qaybood oo dheef-shiid kiimikaad ah: moodooyinka waxay qiyaasayaan in unugyada kansarku ay keenaan wax soo saarka OHB ee fibroblastyada ku xiga, oo bixiya baahida tamarta unugyada unugyada (Bonuccelli et al., 2010; Martinez-Outschoorn et al.,2012). . Beerka, isbeddelka hepatocytes ee ketogenesis ilaa ketone oxidation ee unugyada hepatocellular carcinoma (hepatoma) waxay la socotaa firfircoonida BDH1 iyo hawlaha SCOT ee lagu arkay labada xariiq ee unugyada hepatoma (Zhang et al., 1989). Runtii, unugyada hepatoma waxay muujinayaan OXCT1 iyo BDH1 waxayna oxidize ketones, laakiin kaliya marka serum ay gaajoodaan (Huang et al., 2016). Taas beddelkeeda, ketogenesis unugga burada ayaa sidoo kale la soo jeediyay. Isbeddellada firfircoon ee muujinta hidda-wadaha ketogenic ayaa lagu soo bandhigaa inta lagu jiro isbeddelka kansarka ee epithelium colonic, nooc unug ah oo sida caadiga ah muujiya HMGCS2, iyo warbixin dhowaan ayaa soo jeedisay in HMGCS2 ay noqon karto calaamad muujinaysa saadaal liidata ee kansarka unugyada mindhicirka iyo squamous (Camarero et al., 2006; Chen iyo al., 2016). Haddi ururkani u baahan yahay ama ku lug leeyahay ketogenesis, ama shaqada iftiiminta dayaxa ee HMGCS2, ayaa weli ah in la go'aamiyo. Taa beddelkeeda, muuqata ?soosaarka OHB ee melanoma iyo unugyada glioblastoma, oo ay kicisay PPAR? agonist fenofibrate, ayaa lala xiriiriyay xiritaanka koritaanka (Grabacka et al., 2016). Daraasado dheeraad ah ayaa looga baahan yahay si loo qeexo doorarka HMGCS2/SCOT muujinta, ketogenesis, iyo oksaydhka ketone ee unugyada kansarka.

Marka laga soo tago saaxadda dheef-shiid kiimikaadka shidaalka, ketones ayaa dhowaan lagu lug yeeshay bayoolajiga unugyada kansarka iyada oo loo marayo habka calaamadaynta. Falanqaynta BRAF-V600E+ melanoma waxay muujisay OCT1-ku-tiirsanaanta HMGCL ee habka ku-tiirsanaanta oncogenic BRAF (Kang et al., 2015). Kordhinta HMGCL waxay la xidhiidhay uruurinta AcAc-ga gacanta ee sare, taas oo iyana xoojisay isdhexgalka BRAFV600E-MEK1, kor u qaadaya calaamadaynta MEK-ERK ee loop-horumarin quudin ah oo dhaqaajisa kororka unugyada burooyinka iyo koritaanka. Indho-indhayntani waxay kor u qaadaysaa su'aasha xiisaha leh ee ketogenesis-ka kabaxsanaanta ee ka dibna taageerta habka calaamadaynta (sidoo kale eeg Waxa kale oo muhiim ah in la tixgeliyo saamaynta madax-bannaan ee AcAc, d-?OHB, iyo l-?OHB ee dheef-shiid kiimikaadka kansarka, iyo marka la tixgelinayo HMGCL, catabolism leucine ayaa sidoo kale laga yaabaa in uu xumaado.

Saamaynta cuntooyinka ketogenic (sidoo kale eeg isticmaalka daaweynta ee cuntada ketogenic iyo jidhka ketone dibadda) ee moodooyinka xayawaanka kansarka way kala duwan yihiin (De Feyter et al., 2016; Klement et al., 2016; Meidenbauer et al., 2015; Poff et al. ., 2014; Seyfried iyo al., 2011; Shukla iyo al., 2014). Iyadoo ururada cudurrada faafa ee buurnaanta, kansarka, iyo cuntooyinka ketogenic laga doodayo (Liskiewicz et al., 2016; Wright iyo Simone, 2016), falanqaynta-meta iyadoo la adeegsanayo cuntooyinka ketogenic ee moodooyinka xayawaanka iyo daraasadaha bini'aadamka ayaa soo jeediyay saameyn sal leh oo badbaado leh, oo leh faa'iidooyinka si toos ah ugu xidhan baaxadda ketosis, wakhtiga bilowga cuntada, iyo meesha buro (Klement et al., 2016; Woolf et al., 2016). Daawaynta unugyada kansarka xameetida ee jidhka ketone (d-?OHB ama AcAc) waxay joojisay koritaanka, bararka iyo glycolysis, iyo cuntada ketogenic (81% kcal dufan, 18% borotiin, 1% carbohydrate) hoos u dhac ku ah miisaanka buro vivo, glycemia, iyo korodhka muruqa iyo miisaanka jidhka ee xayawaanka qaba kansarka la beeray (Shukla et al., 2014). Natiijooyin la mid ah ayaa lagu arkay iyadoo la adeegsanayo qaabka unugyada glioblastoma metastatic ee jiirarka helay kabka ketone ee cuntada (Poff et al., 2014). Taa beddelkeeda, cuntada ketogenic (91% dufanka kcal, 9% borotiinka) waxay kordhisay wareegga OHB iyo hoos u dhaca glycemia laakiin wax saameyn ah kuma yeelan labada mugga burada ama muddada badbaadada ee jiirka glioma-sida (De Feyter et al., 2016). Tilmaanta ketone gulukooska ayaa loo soo jeediyay inay tahay tilmaame caafimaad oo hagaajinaysa maaraynta dheef-shiid kiimikaad ee daaweynta kansarka maskaxda ee ketogenic ee bini'aadamka iyo jiirarka (Meidenbauer et al., 2015). Isku soo wada duuboo, doorarka dheef-shiid kiimikaad ee jidhka ketone iyo jidhka ketone ee bayoolajiga kansarka ayaa ah mid isbedbeddelaya sababtoo ah mid kastaa wuxuu keenaa doorashooyin daweyn oo la heli karo, laakiin dhinacyada aasaasiga ah ayaa weli ah in la caddeeyo, iyada oo saameyn cad oo ka soo baxaysa jaantusyada doorsoomayaal, oo ay ku jiraan (i) kala duwanaansho u dhexeeya ketone dibadda ah. jirka oo ka soo horjeeda cuntada ketogenic, (ii) nooca unugyada kansarka, polymorphisms genomic, darajada, iyo heerka; iyo (iii) wakhtiga iyo muddada soo-gaadhista xaalada ketotic.

Ketogenesis waxaa abuuray jidhka ketone iyada oo loo marayo burburka asiidhyada dufanka leh iyo amino acids ketogenic. Nidaamkan biochemical wuxuu tamarta siiya xubnaha kala duwan, gaar ahaan maskaxda, xaaladaha soonka si looga jawaabo la'aanta gulukoosta dhiigga. Jidhka ketone waxaa inta badan laga soo saaraa mitochondria ee unugyada beerka. Halka unugyada kale ay awood u leeyihiin inay fuliyaan ketogenesis, ma aha kuwo waxtar u leh samaynta sidaas sida unugyada beerka. Sababtoo ah ketogenesis wuxuu ku dhacaa mitochondria, hababkeeda si madaxbannaan ayaa loo habeeyaa. Dr. Alex Jimenez DC, CCST Insight

Codsiga daawaynta ee Cunnada Ketogenic iyo Jidhka Ketone-ka Baxsan

Codsiyada cuntooyinka ketogenic iyo jidhka ketone sida qalabka daaweynta ayaa sidoo kale ka soo baxay xaalado aan kansar ahayn oo ay ku jiraan cayilka iyo NAFLD / NASH (Browning et al., 2011; Foster et al., 2010; Schugar iyo Crawford, 2012); wadne xanuunka (Huynh, 2016; Kolwicz et al., 2016; Taegtmeyer, 2016); Cudurka neerfaha iyo neerfaha (Martin et al., 2016; McNally iyo Hartman, 2012; Rho, 2015; Rogawski et al., 2016; Yang iyo Cheng, 2010; Yao et al., 2011); khaladaadka dhashay ee dheef-shiid kiimikaad (Scholl-B�rgi et al, 2015); iyo waxqabadka jimicsiga (Cox et al., 2016). Waxtarka cuntooyinka ketogenic ayaa si gaar ah loogu mahad celiyay daawaynta suuxdinta, gaar ahaan bukaannada u adkaysta daroogada. Daraasadaha intooda badani waxay qiimeeyeen cuntooyinka ketogenic ee bukaannada carruurta, waxayna muujinayaan ilaa ~ 50% hoos u dhigista inta jeer ee suuxdinta ka dib bilaha 3, iyada oo la wanaajiyey waxtarka xulashada cilladaha (Wu et al., 2016b). Waayo-aragnimadu aad ayey u xaddidan tahay suuxdinta qaangaarka ah, laakiin hoos u dhac la mid ah ayaa muuqda, iyada oo jawaab wanaagsan laga helayo bukaannada suuxdinta guud ee calaamadaha (Nei et al., 2014). Hababka hoose ee ka-hortagga gariirku weli ma cadda, in kasta oo mala-awaalka la soo dhejiyay ay ka mid yihiin isticmaalka gulukooska oo yaraaday / glycolysis, gaadiidka glutamate ee dib loo habeeyay, saameyn aan toos ahayn oo ku saabsan kanaalka potassium-xasaasiga ah ee ATP ama adenosine A1 receptor, beddelka muujinta isoform channel sodium, ama saameynta hormoonnada wareegga wareegga oo ay ku jiraan leptin ( Lambrechts iyo al., 2016; Lin et al., 2017; Lutas iyo Yellen, 2013). Ma cadda in saamaynta ka-hortagga qallafsanaantu ay ugu horrayn u nisbeeyeen jidhka ketone, ama ay sabab u tahay cawaaqib-xumada dheef-shiid kiimikaad ee cuntooyinka karbohaydraytyada yar. Si kastaba ha ahaatee, esters ketone (hoos fiiri) waxay u muuqdaan inay kor u qaadayaan heerka suuxdinta ee moodooyinka xayawaanka ee suuxdinta xanaaqa (Ciarlone et al., 2016; D'Agostino et al., 2013; Viggiano et al., 2015).

Atkins-style iyo ketogenic, cuntooyinka karbohaydrayt hooseeya ayaa badanaa loo arkaa kuwo aan fiicnayn, waxayna sababi karaan calool-istaagga, hyperuricemia, hypocalcemia, hypomagnesemia, waxay keenaan nephrolithiasis, ketoacidosis, waxay keenaan hyperglycemia, waxayna kor u qaadaan kolestaroolka wareega iyo uruurinta dufanka bilaashka ah (Bisschop et al., 2001) Kossoff iyo Hartman, 2012; Kwiterovich iyo al., 2003; Suzuki et al., 2002). Sababahan dartood, u hoggaansanaanta muddada dheer waxay keenaysaa caqabado. Daraasadaha jiirarka waxay caadi ahaan adeegsadaan qaybin nafaqo oo gaar ah (94% dufanka kcal, 1% kcal carbohydrate, 5% protein kcal, Bio-Serv F3666), taasoo kicisa ketosis adag. Si kastaba ha noqotee, kordhinta maadada borotiinka, xitaa ilaa 10% kcal waxay si weyn u yaraynaysaa ketosis-ka, iyo 5% xaddidaadda borotiinka kcal waxay keenaysaa jahwareerka dheef-shiid kiimikaadka iyo saameynta jireed. Qaabaynta cuntadan ayaa sidoo kale hoos u dhacday choline, doorsoome kale oo saameeya u nuglaanshaha dhaawaca beerka, iyo xitaa ketogenesis (Garbow et al., 2011; Jornayvaz et al., 2010; Kennedy et al., 2007; Pissios et al., 2013; Schugar iyo al., 2013). Saamaynta isticmaalka muddada-dheer ee cuntooyinka ketogenic ee jiirarka ayaa weli ah mid aan dhammaystirnayn, laakiin cilmi-baaristii ugu dambeysay ee jiirarka ayaa muujisay badbaadada caadiga ah iyo maqnaanshaha calaamadaha dhaawaca beerka ee jiirarka ee cuntooyinka ketogenic ee noloshooda, inkastoo dheef-shiid kiimikaad amino, kharashka tamarta, iyo calaamadaynta insulin si cad ayaa dib loo habeeyey (Douris et al., 2015).

Farsamooyinka kordhinta ketosis iyada oo loo marayo habab ka duwan cuntooyinka ketogenic waxaa ka mid ah isticmaalka horudhacyada jidhka ketone ee la cuni karo. Maamulka jirka ketone ee dibadda ka ah wuxuu abuuri karaa xaalad jireed oo gaar ah oo aan la kulmin physiology caadiga ah, sababtoo ah wareegga wareegga gulukooska iyo uruurinta insulintu waa wax iska caadi ah, halka unugyadu ay dhaafin karaan qaadashada gulukooska iyo ka faa'iidaysiga. Jidhka Ketone laftoodu waxay leeyihiin nolol badhkeed oo gaaban, iyo nuugista ama faleebada sodium ?milix OHB si loo gaadho ketosis daweyn ayaa kicisa culays soodhiyam ah oo aan leexleexan. R/S-1,3-butanediol waa dialcohol aan sun ahayn oo si sahal ah ugu oksaydhsan beerka si ay u dhaliso d/l-?OHB (Desrochers et al., 1992). Xaalado tijaabo ah oo kala duwan, qiyaastan ayaa la siiyay maalin kasta jiirka ama jiirka ilaa todoba toddobaad, taasoo keentay wareegtada? Agostino iyo al., 5). Xakamaynta qayb ka mid ah qaadashada cuntada ayaa lagu arkay jiirka la siiyay R/S-1,3-butanediol (Carpenter and Grossman, 1983). Intaa waxaa dheer, saddex ketone ester (KEs), (i) monoester ee R-1,3-butanediol iyo d-? OHB (R-3-hydroxybutyl R-? OHB); (ii) glyceryl-tris-?OHB; iyo (iii) R, S-1,3-butanediol acetoacetate diester, ayaa sidoo kale si weyn loo bartay (Brunengraber, 1997; Clarke et al., 2012a; Clarke et al., 2012b; Desrochers et al., 1995a; Desrochers et al. ., 1995b; Kashiwaya iyo al., 2010). Faa'iidada asalka ah ee tan hore waa in 2 moles oo ah physiological d-?OHB la soo saaro halkii mole ee KE, ka dib esterase hydrolysis ee xiidmaha ama beerka. Badbaadada, farmashiyaha, iyo dulqaadka ayaa si weyn loogu bartay bini'aadamka qaadashada R-3-hydroxybutyl R-?OHB, qiyaaso ilaa 714 mg/kg, taasoo keenaysa wareegga d-?OHB uruurinta ilaa 6 mM (Clarke et al., 2012a; Cox et al., 2016; Kemper et al., 2015; Shivva et al., 2016). Jiirka, KE-dani waxay hoos u dhigtaa qaadashada kaloriinta iyo wadarta guud ee kolestaroolka, waxay kicisaa nudaha adipose brown, waxayna wanaajisaa iska caabbinta insulin (Kashiwaya et al., 2010; Kemper et al., 2015; Veech, 2013). Natiijooyinki ugu dambeeyay waxay muujinayaan in inta lagu jiro jimicsiga ciyaartoyda loo tababaray, R-3-hydroxybutyl R-? OHB nuugista waxay hoos u dhigtay glycolysis muruqa lafaha iyo plasma lactate, korodhka oxidation triacylglycerol gudaha muruqa, iyo ilaalinta maadada glycogen muruqa, xitaa marka la isku daro karbohaydraytyadu ay kiciyaan dheecaanka insulin Cox iyo al., 2016). Horumarinta dheeraadka ah ee natiijooyinkan xiisaha leh ayaa loo baahan yahay, sababtoo ah hagaajinta waxqabadka jimicsiga dulqaadka ayaa inta badan u horseeday jawaab celin adag oo ku saabsan KE ee maadooyinka 2 / 8. Si kastaba ha ahaatee, natiijooyinkani waxay taageeraan daraasaadka qadiimiga ah ee tilmaamaya doorbidida oksaydhka ketone marka loo eego substrates kale (GARLAND et al., 1962; Hasselbaink et al., 2003; Stanley et al., 2003; Valente-Silva et al., 2015), oo ay ku jiraan inta lagu jiro jimicsiga, iyo in ciyaartooyda la tababaray laga yaabo inay aad ugu fiicnaadaan isticmaalka ketones (Johnson et al., 1969a; Johnson iyo Walton, 1972; Winder et al., 1974; Winder et al., 1975). Ugu dambeyntii, hababka taageeri kara waxqabadka jimicsiga oo la hagaajiyay ka dib qaadashada kalooriyada siman (si kala duwan ayaa loo qaybiyaa nafaqeeyayaalka yar yar) iyo heerka isticmaalka ogsijiinta siman ayaa weli ah in la go'aamiyo.

Aragtida Mustaqbalka

Marka si weyn loo dhaleeceeyo sida dariiq qulqulaya oo awood u leh ururinta sunta ka soo baxda gubashada dufanka ee gobollada xaddidan ee karbohaydraytyada (sida ketotoxic) , indha-indheyntii dhawaa waxay taageertaa fikradda ah in dheef-shiid kiimikaad ee ketone uu u adeego door saliim ah xitaa gobollada karbohaydrayt-ku raran yahay, furitaanka ketohormetic � mala awaal. In kasta oo fududaynta hababka nafaqeynta iyo dawooyinka si loo maareeyo dheef-shiid kiimikaadka ketone ay ka dhigayaan bartilmaameed daweyn soo jiidasho leh, si adag loo soo bandhigay laakiin tijaabooyin taxaddar leh ayaa weli ku jira shaybaarrada cilmi-baarista aasaasiga ah iyo tarjumaada labadaba. Baahida aan la daboolin ayaa ka soo ifbaxday qaybaha qeexida doorka ka faa'iidaysiga dheef-shiid kiimikaadka ketone ee wadna xanuunka, buurnaanta, NAFLD/NASH, nooca 2 ee sonkorowga, iyo kansarka. Baaxadda iyo saamaynta 'aan-canonical-ka-soo-jeedinta' doorarka calaamadaha ketone, oo ay ku jiraan nidaaminta PTM-yada oo ay u badan tahay inay dib iyo hor u sii wadaan dheef-shiid kiimikaadka iyo dariiqyada calaamadaha, waxay u baahan yihiin sahan qoto dheer. Ugu dambeyntii, ketogenesis-ka-baxa ka-baxa wuxuu furi karaa hababka calaamadaynta paracrine iyo autocrine-ta xiisaha leh iyo fursadaha lagu saameynayo isku-dhafka dheef-shiid kiimikaadka gudaha habka dareemayaasha iyo burooyinka si loo gaaro dhammaadka daweynta.

Mahadnaq

Ncbi.nlm.nih.gov/pmc/articles/PMC5313038/

Qoraalada

Ncbi.nlm.nih.gov

Gabagabadii, jirka ketone waxaa abuuray beerka si loogu isticmaalo ilo tamar marka aysan jirin gulukoos ku filan oo diyaar u ah in laga helo jirka bini'aadamka. Ketogenesis-ka waxay dhacdaa marka ay jiraan heerar gulukoos oo hooseeya ee dhiigga, gaar ahaan ka dib marka kaydka karbohaydraytyada gacanta ay daalan yihiin. Ujeedada maqaalka kor ku xusan waxay ahayd in laga hadlo doorarka kala duwan ee jirka ketone ee dheef-shiid kiimikaadka shidaalka, calaamadaynta, iyo daaweynta. Baaxadda macluumaadkayadu waxay ku kooban tahay xanuunka loo yaqaan 'chiropractic' iyo arrimaha caafimaadka laf dhabarta. Si aad ugala hadasho mawduuca, fadlan xor u noqo inaad waydiiso Dr. Jimenez ama nagala soo xidhiidh at�915-850-0900 .

Waxaa soo saaray Dr. Alex Jimenez

Waxaa laga soo xigtay:�Ncbi.nlm.nih.gov/pmc/articles/PMC5313038/

Mawduuc Dheeraad ah: � Xanuun Dhabar Ba'an

Xanuunka dhabarka�waa mid ka mid ah sababaha ugu badan ee naafada iyo maalmaha shaqada ka baaqda ee adduunka oo dhan. Dhabar xanuunka waxa loo aaneynayaa sababta labaad ee ugu badan ee booqashooyinka xafiiska dhakhtarka, oo ay ka badan yihiin kaliya caabuqyada neef-mareenka sare. Qiyaastii 80 boqolkiiba dadku waxay la kulmi doonaan xanuunka dhabarka ugu yaraan hal mar noloshooda oo dhan. Laf-dhabarta waa qaab dhismeed kakan oo ka kooban lafo, kala-goysyo, seedaha, iyo murqaha, iyo unugyo kale oo jilicsan. Dhaawacyada iyo/ama xaaladaha sii xumeeyay, sida�maqaarka herniated, ugu dambeyntii waxay keeni kartaa calaamadaha xanuunka dhabarka. Dhaawacyada isboortiga ama dhaawacyada shilalka baabuurta ayaa inta badan ah sababta ugu badan ee xanuunka dhabarka, si kastaba ha ahaatee, mararka qaarkood dhaqdhaqaaqa ugu fudud ayaa keeni kara natiijooyin xanuun leh. Nasiib wanaag, xulashooyinka daaweynta kale, sida daryeelka xanuunka loo yaqaan 'chiropractic care', ayaa kaa caawin kara yareynta xanuunka dhabarka iyada oo loo marayo isticmaalka isbeddelka laf-dhabarka iyo manfacyada gacanta, ugu dambeyntii hagaajinta xanuunka. �

DHEERAAD AH | Mawduuca MUHIIMKA AH: Lagu taliyay El Paso, TX Chiropractor

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