Ngaba uziva:

ImiSebenzi yeMidi-Dimensional yeeConone zeCetone

by UGqr Alex Jimenez | Ukuguga, Ukuxutyushwa, Ukutya, LweMpilo, impilo, Iindaba zezeMpilo El Paso, Medicine Holistic, I-Ketogenic Diet ichazwe, WeMpilo yeNdalo, isondlo, Uxinzelelo oluxhasayo, ulungiso, Izifundo zoPhando, nezongezo, Unyango, Ukuphila

Imizimba yeKetone yenziwa sisibindi kwaye isetyenziswa njengomthombo wamandla xa i-glucose ingafumaneki lula emzimbeni womntu. Izidumbu ezimbini eziphambili ze-ketone ziyi-acetoacetate (i-AcAc) kunye ne-3-beta-hydroxybutyrate (3HB), ngelixa i-acetone yinto yesithathu kwaye incinci kakhulu, i-ketone body. IiKetones zihlala zikhona egazini kwaye amanqanaba azo anda ngexesha lokuzila ukutya kunye nokuzilolonga ixesha elide.�Ketogenesis yinkqubo ye-biochemical apho iilwanyana zivelisa izidumbu ze-ketone ngokuphuhla kwama-acid acids kunye ne-ketogenic amino acid.

Izidumbu ze-Ketone zenziwe ngokubanzi kwi i-mitochondria yeeseli zesibindi. I-Ketogenesis iyenzeka xa kunamazinga e-glucose aphantsi egazini, ngokukodwa emva kwezinye izityalo ze-carbohydrates stores, ezifana ne-glycogen, ziphelile. Le ndlela iyakwenzeka kwakhona xa kukho inani elaneleyo le-insulin. Ukuveliswa kwamagumbi e-ketone ekugqibeleni kuqaliswe ukwenza amandla atholakalayo agcinwe emzimbeni womntu njenge-fatty acids. I-Ketogenesis ivela kwi-mitochondria apho ilawulwa ngokuzimeleyo.

Abstract

I-ketone body metabolism yiyona node ephambili kwi-homeostasis yomzimba. Kule ngongoma, sixoxa ngendlela ietononi eziqhuba ngayo iindidi ezixubileyo zokucwangcisa ukulungelelanisa ukusebenza komzimba kunye nokusebenza komzimba ngokungafaniyo kwezondlo kunye nokukhusela ekuvukeleni nokulimala kwiinkqubo ezininzi zeenkonzo. Ngokuqhelekileyo kubonwa njengemigweba yezinto ezinomsocolo kuphela ekungqinisweni kwinqumbo ye-carbohydrate, ukuqwalaselwa kwangoko kubonakalisa ukubaluleka kwamagumbi e-ketone njengendlela ebalulekileyo yokuxilisa kunye nabalindi beempawu xa i-carbohydrates ininzi. Ukuzalisekisa kwakhona imifanekiso yonyango eyaziwayo yezifo zesistim se-nervous, iindima eziza kuba yimizimba ye-ketone emdlalweni, sele ikhethileyo inxaxheba kwintliziyo kunye nesibindi, ivula iindlela zokwelapha ezinxulumene nokugqithisa nesifo se-cardiovascular. Iingxabano kwi-ketone metabolism kunye nokubonakaliswa zixutyushwa ukudibanisa imfundiso yeklasi kunye nokuqwalaselwa kwangoku.

intshayelelo

Imizimba yeKetone yenye yezona zinto zibalulekileyo zomthombo wamafutha kuzo zonke iindawo zobomi, i-eukarya, ibhaktheriya, kunye ne-archaea (Aneja et al., 2002; Cahill GF Jr, 2006; Krishnakumar et al., 2008). I-Ketone umzimba wemetabolism ebantwini iye yaxhatshazwa ukuba ifuthe ingqondo ngexesha leepisodic lokunqongophala kwezondlo. Imizimba ye-ketone idityaniswe neendlela ezibalulekileyo zesondlo esanyisayo ezifana ne-?-oxidation (FAO), umjikelo we-tricarboxylic acid (TCA), i-gluconeogenesis, de novo lipogenesis (DNL), kunye ne-biosynthesis ye-sterols. Kwizilwanyana ezanyisayo, imizimba ye-ketone iveliswa kakhulu esibindini ukusuka kwi-FAO-derived acetyl-CoA, kwaye ithuthelwa kwizicubu ze-extrahepatic ze-terminal oxidation. Le physiology ibonelela ngesinye isibaso esongezwa ngamaxesha amafutshane okuzila ukutya, oko kwandisa ukufumaneka kwe-acid enamafutha kunye nokunciphisa ukufumaneka kwe-carbohydrate (Cahill GF Jr, 2006; McGarry and Foster, 1980; Robinson and Williamson, 1980). I-Ketone body oxidation iba ligalelo elibalulekileyo kumandla apheleleyo we-mammalian metabolism ngaphakathi kwezicubu ze-extrahepatic kwiindawo ezininzi ze-physiological, kubandakanywa ukuzila ukutya, indlala, ixesha lokuzala, emva kokuzivocavoca, ukukhulelwa, kunye nokubambelela kwi-carbohydrate ephantsi yokutya. Ukujikeleza i-ketone body concentrations kubantu abadala abasempilweni ngokuqhelekileyo ibonisa i-circadian oscillations phakathi kwe-100�250 �M, ukunyuka ukuya kwi ~ 1 mM emva kokuzivocavoca ixesha elide okanye i-24h yokuzila ukutya, kwaye inokuqokelela ukuya kwi-20 mM kwiimeko ze-pathological ezifana ne-diabetes ketoacidosis. Cahill GF Jr, 2006; Johnson et al., 1969b; Koeslag et al., 1980; Robinson and Williamson, 1980; Wildenhoff et al., 1974). Isibindi somntu sivelisa ukuya kuthi ga kwi-300 g yemizimba ye-ketone ngosuku (i-Balasse kunye ne-Fery, ngo-1989), enegalelo phakathi kwe-5-20% yenkcitho yamandla iyonke kwiindawo ezondlayo, ezizila ukutya, kunye nendlala (Balasse et al., 1978; Cox et al., 2016; Cox et al. al., XNUMX).

Izifundo zakutsha ngoku zibalaselise indima ebalulekileyo kwiimpawu ze-ketone kwi-mammalian cell metabolism, homeostasis, kunye nokubonakaliswa phantsi kweendawo ezahlukeneyo zezobugcisa kunye nezifo. Ngaphandle kokukhonza njengombane wamandla kwiimfucu ze-extrahepatic ezifana nobuchopho, intliziyo, okanye i-squelet muscular, izidumbu ze-ketone zidlala indima ebonakalayo njengokubonisa abalamlamli, abaqhubi beeprotheyini emva kokuguqulela (i-PTM), kunye nabaxhasi be-inflammation kunye nokuxinzezeleka kwengcinezelo. Kule ngongoma, sinika imibono yesibini kunye neyamhlanje yeendima ze-pleiotropic ze-ketone kunye ne-metabolism yazo.

Ubume be-Ketone Body Metabolism

Ireyithi ye-hepatic ketogenesis ilawulwa yi-orchestrated series of physiological and biochemical transformations of fat. Abalawuli abaphambili babandakanya i-lipolysis ye-fatty acids esuka kwi-triacylglycerols, ukuthuthwa ukuya kunye nokunqumla kwi-hepatocyte plasma membrane, ukuthuthwa kwi-mitochondria nge-carnitine palmitoyltransferase 1 (CPT1), i-? kwezi nkqubo, ikakhulu iglucagon kunye ne-insulin [ihlaziywe kwi (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al., 1983; Kahn et al., 2005; McGarry kunye noFoster) , 1980; Williamson et al., 1969)]. Ngokwesiqhelo i-ketogenesis ijongwa njengendlela echithekileyo, apho i-?-i-oxidation-derived acetyl-CoA idlula umsebenzi we-citrate synthase kunye/okanye ukufumaneka kwe-oxaloacetate ukwenzela ukujiyisa ukwenza i-citrate. Abaphakathi kwekhabhoni ezintathu babonisa umsebenzi we-anti-ketogenic, mhlawumbi ngenxa yokukwazi ukwandisa i-oxaloacetate pool yokusetyenziswa kwe-acetyl-CoA, kodwa i-hepatic acetyl-CoA yoxinaniso yodwa ayiqinisi izinga le-ketogenic (Foster, 1967; Rawat kunye neMenahan, 1975; Williamson kunye nabanye, ngo-1969). Ukulawulwa kwe-ketogenesis nge-hormonal, i-transcriptal, kunye neziganeko zasemva kokuguqulelwa kunye zixhasa ingcamango yokuba iindlela ze-molecular ukuba i-fine-tune ketogenic rate zihlala zingaqondwa ngokupheleleyo (jonga i-Regulation ye-HMGCS2 kunye ne-SCOT / OXCT1).

I-Ketogenesis yenzeka ngokuyinhloko kwi-matrix ye-mitochondrial ye-hepatic kumazinga ahambelana ne-oxidation yamafutha. Emva kokuthuthwa kwamatyathanga e-acyl ngaphaya kwe-membrane ye-mitochondrial kunye ne-?-oxidation, i-isoform ye-mitochondrial ye-3-hydroxymethylglutaryl-CoA synthase (HMGCS2) idala i-fate eyenza i-acetoacetyl-CoA (i-AcAc-CoA) kunye ne-acetyl-CoA ye-acetyl-CoA (Umfanekiso 1A). I-HMG-CoA lyase (HMGCL) iqhekeza i-HMG-CoA ukukhulula i-acetyl-CoA kunye ne-acetoacetate (i-AcAc), kwaye le yokugqibela iyancitshiswa ibe yi-d-?-hydroxybutyrate (d-?OHB) nge-phosphatidylcholine-dependent mitochondrial d-?OHB dehydrogenase (? I-BDH1) kwi-NAD +/NADH-idibene kufuphi ne-equilibrium reaction (Bock and Fleischer, 1975; LEHNINGER et al., 1960). I-equilibrium ye-BDH1 rhoqo ithanda ukuveliswa kwe-d-?OHB, kodwa umlinganiselo we-AcAc/d-?OHB imizimba yeketone ihambelana ngokuthe ngqo ne-mitochondrial NAD+/NADH ratio, kwaye ngaloo ndlela umsebenzi we-BDH1 oxidoreductase ulungelelanisa amandla e-mitochondrial redox (Krebs et al., 1969; 1967; Williamson et al., 1929). I-AcAc ingaphinda izenze ngokuzenzekelayo i-decarboxylate kwi-acetone (Pedersen, 7), umthombo wevumba elimnandi kubantu abaphethwe yi-ketoacidosis (oko kukuthi, imizimba ye-serum ketone iyonke> ~3.6 mM; AcAc pKa 4.7, ?OHB pKa 1). Iindlela apho imizimba ye-ketone ithuthwa ngayo kwi-membrane yangaphakathi ye-mitochondrial ayaziwa, kodwa i-AcAc/d-?OHB ikhutshwa kwiiseli ngokusebenzisa abathuthi be-monocarboxylate (kwizilwanyana ezincancisayo, i-MCT 2 kunye ne-16, eyaziwa ngokuba yi-solute carrier 1A amalungu osapho 7 kunye I-2011) kwaye ihanjiswe kwi-circulation kwii-tissue ze-extrahepatic ze-oxidation ye-terminal (Cotter et al., 2012; Halestrap noWilson, 2012; Halestrap, 2012; Hugo et al., 1940). Ukugxininiswa kwemizimba ye-ketone ejikelezayo iphezulu kunezo zikhoyo kwizicubu ze-extrahepatic (i-Harrison kunye ne-Long, i-1) ebonisa ukuba imizimba ye-ketone ihanjiswa phantsi kwe-concentration gradient. Ukulahleka komsebenzi wenguqu kwi-MCTXNUMX kuhambelana nokuvela ngokukhawuleza kwe-ketoacidosis, ebonisa indima ebalulekileyo ekungenisweni komzimba we-ketone.

� Ngaphandle kokuphazamiseka okunokwenzeka kwemizimba ye-ketone kwi-non-oxidative fates (jonga i-Non-oxidative metabolic fates yemizimba ye-ketone), i-hepatocytes ayinakho ukukwazi ukugaya imizimba ye-ketone abayivelisayo. Imizimba ye-Ketone eyenziwe nge-novo ngesibindi (i) i-catabolized kwi-mitochondria ye-extrahepatic tissues ukuya kwi-acetyl-CoA, ekhoyo kumjikelezo we-TCA we-terminal oxidation (Umfanekiso 1A), (ii) iguqulelwe kwi-lipogenesis okanye i-sterol synthesis pathways (ii) Umzobo 1B), okanye (iii) ukhutshelwe kumchamo. Njengolunye uphethiloli olunamandla, imizimba ye-ketone ixutywe ngokukhawuleza entliziyweni, imisipha yethambo kunye nengqondo (Balasse kunye neFery, 1989; Bentourkia et al., 2009; Owen et al., 1967; Reichard et al., 1974; Sultan, 1988 ). Extrahepatic mitochondrial BDH1 catalyzes the reaction first of ?OHB oxidation, iyiguqulela ngasemva AcAc (LEHNINGER et al., 1960; Sandermann et al., 1986). I-cytoplasmic d-?OHB-dehydrogenase (BDH2) ene-20% kuphela yolandelelwano lwesazisi kwi-BDH1 ine-Km ephakamileyo yemizimba ye-ketone, kwaye idlala indima kwi-homeostasis yensimbi (Davuluri et al., 2016; Guo et al., 2006) . Kwi-matrix ye-mitochondrial ye-extrahepatic, i-AcAc ivuliwe kwi-AcAc-CoA ngokutshintshiselana kwe-CoA-moiety esuka kwi-succinyl-CoA kwi-reaction catalyzed by unique mammalian CoA transferase, succinyl-CoA: 3-oxoacid-CoA transferase (SCOT, CoA transferase; ifakwe ngekhowudi yi-OXCT1), ngokusabela kolungelelwaniso olusondeleyo. Amandla asimahla akhutshwe yi-hydrolysis ye-AcAc-CoA inkulu kune-succinyl-CoA, ithanda ukwenziwa kwe-AcAc. Ngaloo ndlela i-ketone body oxidative flux ivela ngenxa yesenzo sobunzima: ukunikezelwa okukhulu kwe-AcAc kunye nokusetyenziswa ngokukhawuleza kwe-acetyl-CoA ngokusebenzisa i-citrate synthase i-AcAc-CoA (+ succinate) ukwakheka kwe-SCOT. Ngokucacileyo, ngokuchasene ne-glucose (i-hexokinase) kunye ne-fatty acids (i-acyl-CoA synthetases), ukusetyenziswa kwemizimba ye-ketone (i-SCOT) kwifom ye-oxidizable ayifuni utyalo-mali lwe-ATP. I-AcAc-CoA thiolase reaction ebuyiselwa umva [i-catalyzed yiyo nayiphi na i-thiolases ye-mitochondrial efakwe kwi-ACAA2 (i-encoding enzyme eyaziwa ngokuba yi-T1 okanye i-CT), i-ACAT1 (i-encoding T2), i-HADHA, okanye i-HADHB] ivelisa iimolekyuli ezimbini ze-acetyl-CoA, abangena kumjikelezo we-TCA (uHersh noJencks, i-1967; iStern et al., 1956; Williamson et al., 1971). Ngexesha le-ketotic states (oko kukuthi, i-serum ketones> 500 �M), imizimba ye-ketone iba negalelo elikhulu kwinkcitho yamandla-kwaye isetyenziswa kwiithishu ngokukhawuleza de kuthathwe okanye kufakwe i-oxidation yenzeke (Balasse et al., 1978; Balasse and Fery, 1989, 1987) ; Edmond et al., 1987). Inxalenye encinci kakhulu yemizimba ye-ketone ephuma kwisibindi inokulinganiswa ngokukhawuleza kumchamo, kwaye ukusetyenziswa kunye namazinga okubuyisela kwakhona yizintso zilingana noxinzelelo lokujikeleza (Goldstein, 1980; Robinson noWilliamson, 1). Ngexesha lee-ketotic states kakhulu (> 2013 mM kwi-plasma), i-ketonuria isebenza njengengxelo ye-semi-quantitative ye-ketosis, nangona ininzi yovavanyo lweklinikhi yemizimba ye-ketone yomchamo ibona i-AcAc kodwa kungekhona? OHB (Klocker et al., XNUMX).

Iziseko ze-Ketogenic kunye neMpembelelo yazo kwi-Hepatocyte Metabolism

I-substrates ze-Ketogenic ziquka i-fatty acids kunye nama-amino acids (umzobo 1B). I-catabolism yama-amino acids, ngakumbi i-leucine, ivelisa nge-4% yamalungu e-ketone kwi-post-absorption state (Thomas et al., 1982). Ngaloo ndlela i-acetyl-CoA i-substrate echibini yokuvelisa i-ketone imizimba iphuma kwi-acid acids, kuba ngexesha lamazwe anikezela nge-carbohydrates supply, i-pyruvate ingena kumjikelezo we-TCA we-hepatic ngokuyinhloko nge-aplerosis, oko kukuthi, i-ATP-dependence carboxylation kwi-oxaloacetate (OAA), okanye i-malate (I-MAL), kwaye ayikho i-decarboxylation ye-oxidative kwi-acetyl-CoA (i-Jeoung et al., I-2012; i-Magnusson et al., I-1991; i-Merritt et al., I-2011). Ngesibindi, i-glucose kunye ne-pyruvate inika isandla ngokungathandeki kwi ketogenesis, nangona i-pyruvate decarboxylation kwi-acetyl-CoA iphezulu (Jeoung et al., 2012).

I-Acetyl-CoA iqhubeka neendidi ezininzi ezibandakanya i-hepatic intermediary metabolism ngaphaya kwesizukulwane se-ATP ngokusebenzisa i-oxidation yesigxina (kwakhona ubone Ukuhlanganiswa kwe-ketone body metabolism, ukuguqulwa kwesithuba sokuguqulela emva, kunye ne-physiological cell). I-Acetyl-CoA isebenza ngokugqithiseleyo (i) i-pyruvate carboxylase (i-PC), ngaloo ndlela isebenzise indlela yokulawulwa kwemigodi eyenza i-intlerotic yokungena kweemetabolites kumjikelezo we-TCA (i-Owen et al., I-2002; i-Scrutton ne-Utter, i-1967) kunye (ii) ne-pyruvate dehydrogenase i-kinase, e-phosphorylates kwaye inqanda i-pyruvate dehydrogenase (PDH) (Cooper et al., i-1975), ngokuqinisekileyo ukuphucula ukuhamba kwe-pyruvate kumjikelezo we-TCA nge-aplerosis. Ngaphezu koko, i-cytoplasmic acetyl-CoA, enezixhobo ezinokuguqula i-acetyl-CoA kwi-metabolite ezithuthwayo, inqanda i-oxidation e-fatty acid: i-acetyl-CoA carboxylase (i-ACC) iguqula ukuguqulwa kwe-acetyl-CoA kwi-malonyl-CoA, i-lipogenic substrate kunye ne-allosteric inhibitor ye-CPT1 ye-mitochondrial [yahlaziywa ku (Kahn et al., 2005; McGarry noFoster, 1980)]. Ngaloo ndlela, i-mitochondrial-acetyl-CoA echibini ilawula kwaye ilawulwa yindlela ye-ketogenesis, eyenza iindawo eziphambili ze-metabolism eziphambili ze-hepatic.

Iifom zeMetabolic yeeMetoneli zeMetone

Ixesha eliphambili le-ketoni ezifumaneka kwi-fox-derivated oxidation. Nangona kunjalo, i-AcAc ingahanjiswa ngaphandle kwe-mitochondria kwaye isetyenziswe kwiindlela ze-anabolic ngokuguqulwa kwi-AcAc-CoA ngempendulo exhomekeke kwi-ATP eyenziwa yi-cytoplasmic acetoacetyl-CoA synthetase (AACS, Fig. 1B). Le ndlela isebenza ngexesha lokuphuculwa kwengqondo kunye nokukhwabanisa imilenze (Morris, 2005; uRobinson noWillion, 1978; Ohgami et al., 2003). I-AACS iphinda ichazwe kakhulu kwiisitives, kwaye i-osteoclasts esebenzayo (Aguilo et al., 2010; Yamasaki et al., 2016). I-Cytoplasmic AcAc-CoA inokuthi ibhekiswe yi-cytosolic HMGCS1 kwi-bioreynthesis ye-sterol, okanye ifakwe kwi-thietyses ye-acetyl-CoA (ACAA1 kunye ne-ACAT2), i-carboxylated kwi-malonyl-CoA, kwaye ifake isandla kwi-synthesis acid acids (i-Bergstrom et i-1984; u-Edmond, i-1974; i-Endemann et al., i-1982; i-Geelen et al., i-1983; i-Webber ne-Edmond, i-1977).

Nangona ukubaluleka kwe-physiological kuseza kusekwa, ii-ketones zinokusebenza njenge-anabolic substrates nakwisibindi. Kwimixholo yovavanyo eyenziweyo, i-AcAc inokuba negalelo ukuya kuthi ga kwisiqingatha se-lipid esandula ukwenziwa, kwaye ukuya kuthi ga kwi-75% ye-cholesterol entsha eyenziweyo (Endemann et al., 1982; Geelen et al., 1983; Freed et al., 1988). Ngenxa yokuba i-AcAc ivela kwi-oxidation ye-hepatic engaphelelanga, ukukwazi kwe-AcAc ukufaka isandla kwi-lipogenesis kwi-vivo kuya kuthetha ukukhwela ibhayisekile engenamsebenzi, apho ii-ketones ezithathwe ngamanqatha zingasetyenziselwa ukuveliswa kwe-lipid, ingcamango ebaluleke kakhulu kwi-physiological ifuna ukuqinisekiswa kovavanyo, kodwa inokusebenza. iindima eziguqukayo okanye ezingalunganga (uSolinas et al., 2015). I-AcAc ibonelela nge-cholesterogenesis, kunye ne-AACS ephantsi ye-Km-AcAc (~50 �M) ithanda ukusebenza kwe-AcAc nakwilizwe elondliwe (Bergstrom et al., 1984). Indima eguquguqukayo ye-cytoplasmic ketone metabolism iye yacetyiswa kwi-primary mouse embryonic neurons kunye ne-3T3-L1 ephuma kwi-adipocytes, njengoko i-AACS i-knockdown idityanisiwe yokwahlula kohlobo ngalunye lweseli (Hasegawa et al., 2012a; Hasegawa et al., 2012b). I-Knockdown ye-AACS kwiimpuku kwi-vivo iyancipha i-cholesterol ye-serum (Hasegawa et al., 2012c). I-SREBP-2, i-master transcriptional regulator ye-cholesterol biosynthesis, kunye ne-peroxisome proliferator activated receptor (PPAR)-? zi-activators ze-AACS zombhalo, kwaye zilawula ukubhaliswa kwayo ngexesha lophuhliso lwe-neurite kunye nesibindi (Aguilo et al., 2010; Hasegawa et al., 2012c). Kuthatyathwe kunye, i-cytoplasmic ketone body metabolism inokubaluleka kwiimeko ezikhethiweyo okanye kwimbali yendalo yesifo, kodwa akwanelanga ukulahla imizimba ye-ketone ephuma kwisibindi, njengoko i-hyperketonemia enkulu yenzeke kwisimo sokukhubazeka okukhethiweyo kweyona nto iphambili ye-oxidative ngokulahleka kokuguqulwa komsebenzi. ukuya eSCOT (Berry et al., 2001; Cotter et al., 2011).

Ummiselo we-HMGCS2 kunye ne-SCOT / OXCT1

Ukungafani kwe-mitochondrial kwi-gene encoding i-cytosolic HMGCS kwenzeka ekuqaleni kwe-vertebrate evolution ngenxa yentswelo yokuxhasa i-ketogenesis ye-hepatic kwiintlobo ezineengqondo eziphezulu ukuya kubunzima bomzimba (Boukaftane et al., 1994; iCunnane ne-Crawford, i-2003). I-HMGCS2 iinguqulelo ebantwini kubangela ukulahleka kwe-hypoglycemia (hypnetotic hypoglycemia) (Pitt et al., 2015; Thompson et al., 1997). I-Robust HMGCS2 ibinzana kuphela, kwaye i-epitlium ye-colonic, kunye ne-enzymatic activity iboniswe ngeendlela ezahlukeneyo (iMascaro et al., 1995; uMcGarry kunye noFoster, 1980; uRobinson noWillionon, i-1980). Nangona iimeko ezipheleleyo zezinto eziphilayo zichaphazela ukuba i-HMGCS2 idinga ukuhlengahlengiswa, ukubonakaliswa kwayo kunye / okanye umsebenzi ulawulwa ngexesha lokuzalwa emva kokubeleka, ukuguga, isifo sikashukela, indlala okanye ukungena kokutya kwe-ketogenic (i-Balasse ne-Fery, i-1989; i-Cahill GF Jr, i-2006 ; Girard et al., 1992; Hegardt, 1999; iSatapati et al., 2012; iSengupta et al., 2010). Kwi-fetus, i-methylation ye-5� ye-flanking ye-Hmgcs2 gene ihambelana ngokungafaniyo kunye nombhalo wayo, kwaye iguqulwa ngokuyinxenye emva kokuzalwa (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al., 1983; Ayte et al., XNUMX; Ehara et al., XNUMX; Ferre et al. ., XNUMX). Ngokufanayo, i-Bdh1 eneempembelelo ibonisa ipateni yokubonakalisa intuthuko, ikhula ukusuka ekuzaleni ukuya ekutheni, kwaye iqhutywe yindlela yokutya ye-ketogenic kwi-fibroblast yokukhula (FGF) -XXMUMX-dependence (Badman et al., 21; Zhang et al., 2007 ). I-Ketogenesis kwizilwanyana ezincelisayo ziphendula kakhulu kwi-insulin kunye ne-glucagon, ikhutshwe kwaye ivuselelwe, ngokulandelanayo (McGarry noFoster, 1977). I-insulin igxotha i-lipolysis ye-adipose yamathambo, ngaloo ndlela iyanqanda i-ketogenesis ye-substrate yayo, ngoxa i-glucagon ikwandisa i-ketogenic flux ngokuchaphazela ngqo isibindi (Hegardt, 1999). I-Hmgcs2 yoshicilelo ishukunyiswa yi-forkhead ye-transcriptional factor FOXA2, inqatshelwe nge-insulin-phosphatidylinositol-3-kinase / Akt, kwaye ibangelwa yi-glucagon-cAMP-p300 ukubonisa (Arias et al., 1995; Hegardt, 1999; , 1990; Thumelin et al., 1993; von Meyenn et al., 2013; Wolfrum et al., 2004; Wolfrum et al., 2003). PPAR? (Rodriguez et al., 1994) kunye nethagethi yayo, i-FGF21 (u-Badman et al., 2007) iphinda ifake i-Hmgcs2 ukubhalwa kwesibindi ngexesha lendlala okanye ulawulo lokutya kwe-ketogenic (Badman et al., 2007; Inagaki et al., 2007) ). Ukuqaliswa kwePPAR? inokuthi yenzeke ngaphambi kokuba utshintsho olusuka kwi-fetal ukuya kwi-physiology ye-neonatal, ngelixa i-FGF21 isebenze inokuthi ithandeke kwixesha lokuqala le-neonatal nge-?OHB-mediated inhibition ye-histone deacetylase (HDAC) -3 (Rando et al., 2016). i-mTORC1 (ithagethi ye-mammalian ye-rapamycin complex 1) ixhomekeke kwisithintelo se-PPAR? umsebenzi wokubhaliweyo kwakhona umlawuli ophambili we-Hmgcs2 gene expression (Sengupta et al., 2010), kunye nesibindi PER2, i-master circadian oscillator, ilawula ngokungathanga ngqo intetho ye-Hmgcs2 (Chavan et al., 2016). Ukuqwalaselwa kwamva nje kubonisa ukuba i-interleukin-6 ye-tumor ye-extrahepatic iphazamisa i-ketogenesis nge-PPAR? ukucinezelwa (Flint et al., 2016).

Umsebenzi we-HMGCS2 umsebenzi we-enzyme ulawulwa ngePTM ezininzi. I-HMGCS2 i-serine phosphorylation yandise umsebenzi wayo kwi-vitro (iGrimsrud et al., 2012). Umsebenzi we-HMGCS2 unqatshelwe ngokulandelana kwe-succinyl-CoA kunye ne-lysine asele ekutshintsheni (Arias et al., 1995; Hegardt, 1999; iLowe neTubbs, i1985; i-1990; i-RN et al., I-2013; iRed et al. 1975; Thumelin et al., 1993). Ukuphumelela kwe-HMGCS2, i-HMGCL kunye ne-BDH1 i-lysine i-litoine i-mitochondria ye-hepatic iinjongo ze-NAD + exhomekeke ku-deacylase sirtuin 5 (SIRT5) (Rardin et al., 2013). Umsebenzi we-HMGCS2 uphinde ukhutshwe yi-SIRT3 ye-diacetylation ye-lysine, kwaye kungenzeka ukuba i-crosstalk phakathi kwe-acetylation kunye ne-succinylation ilawula umsebenzi we-HMGCS2 (Rardin et al., 2013; Shimazu et al., 2013). Nangona ubuchule bee-PTM zilawula i-HMGCS2 Km kunye ne-Vmax, ukuguqulwa kwale PTM akukabikwa ngokukodwa kwaye akuzange kuqinisekiswe njengabaqhubi bemishini ye ketogenesis kwi vivo.

I-SCOT iboniswa kuzo zonke iiseli zamammalia eziphethe i-mitochondria, ngaphandle kweeypatocytes. Ukubaluleka komsebenzi we-SCOT kunye ne-ketolysis kuboniswe kwiimfucuza ze-SCOT-KO, ezibonakalise ukubulala okufanako ngenxa ye-hypoglycemia ye-hyperketonemic ngaphakathi kwe-48h emva kokuzalwa (iCotter et al., 2011). Ukulahleka kweTissue-ye-SCOT kwi-neurons okanye kwi-myocytes yamathambo kukhuthaza ukungonakali kwamandla ngexesha lendlala kodwa ayibulali (Cotter et al., 2013b). Kubantu, ukulahlekelwa kwe-SCOT kudala kwasekuqaleni ebomini kunye ne-ketoacidosis enzima, kubangele ukunyuka, ukuhlanza kunye ne-coma (i-Berry et al., I-2001; iFukao et al., I-2000; i-Kassovska-Bratinova et al., I-1996; i-Niezen-Koning et al. , I-1997; i-Saudubray et al., I-1987; i-Snyderman et al., I-1998; iTildon kunye ne-Cornblath, i-1972). Incinci encinci iyaziwa kwinqanaba leselula malunga ne-SCOT yegciwane kunye neeprotheyini zolawulo. I-Oxct1 imbonakalo ye-MRNA kunye neprotheni ye-SCOT kunye nomsebenzi wancipha kwiindawo ze-ketotic, mhlawumbi ngeendlela ezixhomekeke kwi-PPAR (iFenselau ne-Wallis, i1974; iFenselau kunye neWallis, i1976; i-1986; i-1991; i-2001; i-Turko et al ., 2010; Wentz et al., 1). Kwi-ketoacidosis yesifo sikashukela, ukungafani phakathi kwe-ketogenesis ye-hepatic kunye ne-oxidation ye-extrahepatic iyancipha ngakumbi ngumsebenzi we-SCOT. Ukugqithisa ngokugqithisileyo kwe-insulin-independent independent carporator (GLUT2 / SLC1A1) kwi-cardiomyocytes inqanda intetho ye-Oxct2009 kunye ne-downregulates i-ketoni ye-oxidation yesigxina kwi-non-ketotic state (Yan et al., 1). Esibindi, i-Oxct122 mRNA ininzi ixhaswa yi-microRNA-3 kunye ne-histone methylation i-H27K3me2011 ebonakalayo ngexesha lokutshintsha ukusuka kwintsholongwane ukuya kwixesha lokubeletha (Thorrez et al., 1). Nangona kunjalo, ukuxhaswa kwegama le-Oxct1 ye-hepatic kwixesha lokubeleka lixhomekeke ekuphumeni kwe-Oxct1-ebonisa i-hematopoietic progenitors esesibindi, kunokuba ilahlekelwe yintetho ye-Oxct1 esele ikhona kwi-hepatocytes eyahlukana. Enyanisweni, ukubonakaliswa kweprotheni ye-Oxct2008 mRNA kunye ne-SCOT kuma-hepatocytes ahluke kakhulu (Orii et al., XNUMX).

I-SCOT ikwalawulwa ziiPTMs. I-enzyme i-hyper-acetylated kwiingqondo ze-SIRT3 KO iigundane, ezibonisa kwakhona ukunciphisa imveliso ye-AcAc exhomekeke kwi-acetyl-CoA (Dittenhafer-Reed et al., 2015). I-nitrate engeyiyo-enzymatic yeentsalela ze-tyrosine ze-SCOT iphinda igxininise umsebenzi wayo, oye waxelwa kwiintliziyo zeemodeli ezahlukeneyo zesifo seswekile (Marcondes et al., 2001; Turko et al., 2001; Wang et al., 2010a). Ngokwahlukileyo, i-tryptophan residue nitration yongeza umsebenzi weSCOT (Br�g�re et al., 2010; Rebrin et al., 2007). Iinkqubo zeemolekyuli zentsalela-i-nitration ethile okanye i-de-nitration eyilelwe ukumodareyitha umsebenzi we-SCOT inokubakho kwaye ifuna ukucaciswa.

Iingxabano kwi-Extrahepatic Ketogenesis

Kwizilwanyana ezincancisayo i-primary organ ketogenic isibindi, kwaye kuphela i-hepatocytes kunye neeseli ze-gut epithelial zivakalisa kakhulu i-isoform ye-mitochondrial ye-HMGCS2 (Cotter et al., 2013a; Cotter et al., 2014; McGarry kunye noFoster, 1980; Robinson, Robinson noWilliamson) . I-Anaerobic bacterial fermentation ye-polysaccharides eyinkimbinkimbi ivelisa i-butyrate, efunnwe yi-colonocytes kwizilwanyana ezincelisayo kwi-terminal oxidation okanye i-ketogenesis (i-Cherbuy et al., 1980), enokuthi idlale indima ekuhlukeni kwekholonocyte (Wang et al., 1995). Ngaphandle kweeseli ze-epithelial ze-gut kunye ne-hepatocytes, i-HMGCS2016 iphantse ingekho phantse kuzo zonke ezinye iiseli ze-mammalian, kodwa ithemba le-ketogenesis ye-extrahepatic liye laphakanyiswa kwiiseli ze-tumor, i-astrocytes yenkqubo ye-nervous central, intso, i-pancreatic ? iiseli, i-retinal pigment epithelium (RPE), kunye nakwi-skeletal muscle (Adijanto et al., 2; Avogaro et al., 2014; El Azzouny et al., 1992; Grabacka et al., 2016; Kang et al., 2016) ; Le Foll et al., 2015; Nonaka et al., 2014; Takagi et al., 2016a; Thevenet et al., 2016; Zhang et al., 2016). I-Ectopic HMGCS2011 iye yabonwa kwizicubu ezingenayo amandla e-ketogenic (Cook et al., 2; Wentz et al., 2016), kunye ne-HMGCS2010 ibonisa imisebenzi ye-ketogenesis-ezimeleyo yokukhanya kwenyanga, kubandakanywa phakathi kwe-nucleus yeseli (Chen et al. , 2; Kostiuk et al., 2016; Meertens et al., 2010).

Naziphi na izicubu ze-extrahepatic ezikhupha imizimba ye-ketone nazo ziyakwazi ukuqokelela imizimba ye-ketone ngokusebenzisa iindlela ezizimeleyo ze-HMGCS2 (umzobo 2A). Nangona kunjalo, akukho zicubu ze-extrahepatic apho ugxininiso lomzimba we-ketone oluzinzileyo ludlula oko kumjikelezo (Cotter et al., 2011; Cotter et al., 2013b; Harrison and Long, 1940), egxininisa ukuba imizimba ye-ketone ihanjiswa phantsi. i-concentration gradient ngokusebenzisa iindlela ezixhomekeke kwi-MCT1/2. Enye indlela ye-extrahepatic ketogenesis ebonakalayo inokubonakalisa ukukhubazeka okuhambelana ne-ketone oxidation. Iinkcazo ezongezelelweyo ezinokubakho ziwela ngaphakathi kwendawo yokubunjwa komzimba we-ketone. Okokuqala, i-de novo ketogenesis inokuthi yenzeke ngomsebenzi oguqulwayo we-enzymatic we-thiolase kunye ne-SCOT (i-Weidemann kunye ne-Krebs, i-1969). Xa i-concentration ye-acetyl-CoA iphezulu kakhulu, iimpendulo eziqhelekileyo ezinoxanduva lwe-AcAc oxidation zisebenza kwicala elingasemva (GOLDMAN, 1954). Indlela yesibini yenzeka xa ?-i-oxidation-derived intermediates iqokelelana ngenxa yebhottleneck yomjikelo we-TCA, i-AcAc-CoA iguqulelwa kwi-l-?OHB-CoA nge-reaction catalyzed by mitochondrial 3-hydroxyacyl-CoA dehydrogenase, kwaye ngokuqhubekayo nge-3-hydroxybutyryl I-CoA deacylase ukuya kwi-l-?OHB, engaqondakaliyo nge-mass spectrometry okanye i-resonance spectroscopy evela kwi-physiological enantiomer d-?OHB (Reed kunye ne-Ozand, 1980). I-l-?OHB inokwahlulwa ngokwe-chromatographically okanye nge-enzymatic ukusuka kwi-d-?OHB, kwaye ikhona kwizicubu ze-extrahepatic, kodwa kungekhona kwisibindi okanye igazi (Hsu et al., 2011). I-Hepatic ketogenesis ivelisa kuphela i-d-?OHB, ekuphela kwe-enantiomer eyi-BDH substrate (Ito et al., 1984; uLincoln et al., 1987; Reed no-Ozand, 1980; Scofield et al., 1982; Scofield et al., 1982). Indlela yesithathu ezimeleyo ye-HMGCS2 yenza i-d-?OHB ngokusebenzisa i-amino acid catabolism, ngakumbi leyo ye-leucine kunye ne-lysine. Indlela yesine ibonakala kuphela ngenxa yokuba ingenxa ye-artifact yokulebula kwaye ibizwa ngokuba yipseudoketogenesis. Le nto ibangelwa ukuguqulwa kwe-SCOT kunye ne-thiolase reactions, kwaye inokubangela ukugqithisa kwe-ketone body turnover ngenxa ye-isotopic dilution ye-ketone body tracer kwi-extrahepatic tissue (Des Rosiers et al., 1990; Fink et al., 1988) . Nangona kunjalo, i-pseudoketogenesis isenokungahoywa kwiimeko ezininzi (Bailey et al., 1990; Keller et al., 1978). I-schematic (Umfanekiso we-2A) ubonisa indlela eluncedo yokufaka isicelo ngelixa uqwalasela i-tissue ephakamileyo yoxinaniso lwe-ketones.

� Izintso mva nje zifumene ingqwalasela njengelungu elinokubakho ketogenic. Kuninzi lwamazwe, intso ngumthengi onayo imizimba yeketone ephuma kwisibindi, ikhupha okanye iphinda ikhuphe imizimba yeketone egazini, kwaye izintso aziyiyo i-net ketone body generator okanye i-concentrator (Robinson noWilliamson, 1980). Ababhali bophononongo lweklasi baphetha ukuba i-ketogenesis encinci ye-renal elinganisiweyo kwinkqubo yovavanyo eyenziweyo yayingahambelani ne-physiologically (Weidemann kunye ne-Krebs, i-1969). Kutshanje, i-renal ketogenesis ifakwe kwi-diabetic kunye ne-autophagy yokunqongophala kwemouse yeemodeli, kodwa kunokwenzeka ukuba i-multi-organ shifts kwi-homeostasis ye-metabolic iguqule i-ketone metabolism edibeneyo ngamagalelo kumalungu amaninzi (Takagi et al., 2016a; Takagi et al., 2016b; Zhang et al., 2011). Olunye upapasho lwakutsha nje lucebise i-renal ketogenesis njengendlela ekhuselayo yokulimala kwe-ischemia-reperfusion kwizintso (Tran et al., 2016). Ugxininiso lwemeko oluzinzileyo lwe-?OHB olusuka kwizicatshulwa zeethishu zezintso zeempuku luxelwe ku ~4�12 mM. Ukuvavanya ukuba ingaba oku kuyabambeka na, silinganise ?Ugxininiso lwe-OHB kwiincindi zentso ezisuka kwi-feed kunye ne-24h ezila ukudla iimpuku. ISerum ?Uxinzelelo lwe-OHB lonyukile ukusuka ~100 �M ukuya kwi-2 mM ngokuzila ukudla okuyi-24h (Umfanekiso 2B), ngelixa uzinzo lwezintso ?Uxinzelelo lwe-OHB lumalunga ne-100 �M kwimeko yokutya, kwaye kuphela yi-1 mM kwimo yokuzila ye-24h (Fig. 2C�E), imigqaliselo ehambelana nogxininiso olubalwe kwiminyaka engama-45 eyadlulayo (Hems and Brosnan, 1970). Kuhlala kunokwenzeka ukuba kwi-ketotic states, imizimba ye-ketone ephuma kwisibindi ingaba yi-renoprotective, kodwa ubungqina be-renal ketogenesis bufuna ukuxhaswa okungakumbi. Ubungqina obubambekayo obuxhasa i-ketogenesis ye-extrahepatic yangempela yaboniswa kwi-RPE (Adijanto et al., 2014). Olu tshintsho lwemetabolism lunomdla lwacetyiswa ukuba luvumele iiketone ezivela kwi-RPE ukuba zihambe ziye kwi-photoreceptor okanye kwiiseli ze-Mller glia, ezinokunceda ekuhlaziyweni kwecandelo langaphandle le-photoreceptor.

?OHB njengoMqondiso woMqondiso

Nangona zizityebi ngamandla, imizimba ye-ketone yenza i-provocative �non-canonical� yokubonakalisa indima kwi-homeostasis yeselula (Umfanekiso 3) (uNewman noVerdin, i-2014; uRojas-Morales et al., 2016). Umzekelo, ?I-OHB inqanda i-HDACs yeKlasi I, eyonyusa i-histone acetylation kwaye ngaloo ndlela ikhuthaze ukubonakaliswa kofuzo olunciphisa uxinzelelo lwe-oxidative (Shimazu et al., 2013). ?OHB ngokwayo i-histone covalent modifier kwiintsalela ze-lysine kwizibindi zokuzila ukutya okanye i-streptozotocin eyenzelwe iimpuku zesifo seswekile (Xie et al., 2016) (kwakhona jonga ngezantsi, Ukudityaniswa kwe-ketone yomzimba we-metabolism, ukuguqulwa kwe-post-translation, kunye ne-cell physiology, kunye Imizimba yeKetone, uxinzelelo lwe-oxidative, kunye ne-neuroprotection).

?I-OHB ikwasebenza ngokusebenzisa i-G-protein coupled receptors. Ngeendlela ezingacacanga zeemolekyuli, icinezela umsebenzi wenkqubo ye-nervous enovelwano kwaye inciphisa inkcitho yamandla iyonke kunye nesantya sentliziyo ngokunqanda umqondiso omfutshane we-fatty acid nge-G protein edibene ne-receptor 41 (GPR41) (Kimura et al., 2011). Enye yezona ziphumo zifundiswayo zokubonisa i-?OHB iqhubeka nge-GPR109A (ekwaziwa ngokuba yi-HCAR2), ilungu le-hydrocarboxylic acid GPCR sub-family echazwe kwizicubu ze-adipose (ezimhlophe kunye ne-brown) (Tunaru et al., 2003), kunye iiseli zomzimba (u-Ahmed et al., 2009). ?OHB kuphela kwe-endogenous ligand eyaziwayo ye-GPR109A receptor (EC50 ~770 �M) eyenziwe yasebenza ngu-d-?OHB, l-?OHB, kunye ne-butyrate, kodwa hayi i-AcAc (Taggart et al., 2005). Umyinge wogxininiso ophezulu we-GPR109A usebenze ufezekiswa ngokuthotyelwa kokutya kwe-ketogenic, indlala, okanye ngexesha le-ketoacidosis, ekhokelela ekuvinjweni kwe-adipose tissue lipolysis. Impembelelo ye-anti-lipolytic ye-GPR109A iqhubela phambili ngokuvinjelwa kwe-adenylyl cyclase kunye nokuncipha kwe-cAMP, inhibiting i-hormone ebucayi ye-triglyceride lipase (Ahmed et al., 2009; Tunaru et al., 2003). Oku kudala i-loop yengxelo engalunganga apho i-ketosis ibeka i-modulatory brake kwi-ketogenesis ngokunciphisa ukukhutshwa kwe-fatty acids engabonakaliyo kwi-adipocytes (u-Ahmed et al., 2009; Taggart et al., 2005), umphumo onokuthi ulungelelaniswe ngu idrive enovelwano evuselela i-lipolysis. I-Niacin (i-vitamin B3, i-nicotinic acid) inamandla (EC50 ~ 0.1 �M) ligand ye-GRP109A, isetyenziswe ngokufanelekileyo amashumi eminyaka ye-dyslipidemias (Benyo et al., 2005; Benyo et al., 2006; Fabbrini et al., 2010; Lukasova et al., 2011; Tunaru et al., 2003). Nangona i-niacin iphucula ukuthuthwa kwe-cholesterol eguqukayo kwi-macrophages kwaye inciphisa izilonda ze-atherosclerotic (Lukasova et al., 2011), iziphumo ze-?OHB kwizilonda ze-atherosclerotic zihlala zingaziwa. Nangona i-GPR109A i-receptor yenza iindima zokukhusela, kwaye unxibelelwano oluthakazelisayo lukhona phakathi kokusetyenziswa kwe-ketogenic yokutya kwi-stroke kunye nezifo ze-neurodeergenerative (Fu et al., 2015; Rahman et al., 2014), indima yokukhusela ye-?OHB nge-GPR109A ayizange iboniswe kwi-vivo .

Okokugqibela, i-?OHB inokuchaphazela ukuthanda ukutya kunye nokuhlutha. Uhlalutyo lwe-meta lwezifundo ezilinganisa imiphumo ye-ketogenic kunye nokutya okuphantsi kakhulu kwamandla kwagqiba ukuba abathathi-nxaxheba abasebenzisa ezi zidlo babonisa ukuhlutha okuphezulu, xa kuthelekiswa nokulawula ukutya (Gibson et al., 2015). Nangona kunjalo, ingcaciso ebambekayo malunga nesi siphumo zezongezelelweyo zemetabolism okanye iihomoni ezinokuguqula umdla wokutya. Umzekelo, iimpuku ezigcinwe kwi-rodent ketogenic diet zibonise ukunyuka kwenkcitho yamandla xa kuthelekiswa neempuku ezityiswayo ezilawulwayo, nangona i-caloric intake efanayo, kunye ne-leptin ejikelezayo okanye i-peptides elawula ukuziphatha kokutyisa ayizange iguqulwe (Kennedy et al., 2007). Phakathi kweendlela ezicetywayo ezicebisa ukuthotywa kokutya yi-?OHB ibandakanya zombini umqondiso kunye ne-oxidation (Laeger et al., 2010). I-Hepatocyte ecacileyo yokususwa kwe-circadian gene gene (Per2) kunye ne-chromatin immunoprecipitation studies ibonise ukuba i-PER2 isebenze ngokuthe ngqo i-Cpt1a gene, kwaye ilawula ngokungathanga ngqo i-Hmgcs2, ekhokelela kwi-ketosis ephazamisekileyo kwiigundane ze-Per2 (Chavan et al., 2016). Ezi mpuku zibonise ulindelo lokutya olonakalisayo, oluye lwabuyiselwa ngokuyinxenye lulawulo lwenkqubo ye-?OHB. Izifundo zexesha elizayo ziya kufuneka ukuba ziqinisekise inkqubo ye-nervous central njengendlela echanekileyo ye-?OHB ekujoliswe kuyo, kwaye ingaba i-ketone oxidation iyadingeka kwimiphumo ebonwayo, okanye ingaba enye indlela yokubonakalisa ibonakaliso ibandakanyeka. Abanye abaphandi baye bacela ukuba kunokwenzeka kwi-astrocyte-derived ketogenesis ngaphakathi kwe-hypothalamus ye-ventromedial njengomlawuli wokutya okutyayo, kodwa olu qwalaselo lwangaphambili luya kuzuza kwiimvavanyo ezisekelwe kwimfuza kunye ne-flux (Le Foll et al., 2014). Ubudlelwane phakathi kwe-ketosis kunye nokunqongophala kwezondlo kuhlala kunomdla kuba indlala kunye nokuhlutha zizinto ezibalulekileyo kwiinzame zokulahlekelwa ubunzima.

Ukuhlanganiswa kweMetabolism ye-Ketone Body, i-Post-Translation, kunye ne-Cell Physiology

Izidumbu ze-Ketone zinegalelo kumachibi ase-acetyl-CoA, i-intermediate ephambili ebonisa imisebenzi ebonakalayo kwi-cell metabolism (Pietrocola et al., 2015). Inxaxheba enye ye-acetyl-CoA kukuba isebenze njenge-substrate ye-acetylation, i-histone covalent-modified enzymatically-catalyised histone (Choudhary et al., 2014; Dutta et al., 2016; Fan et al., 2015; Menzies et al., 2016 ). Ininzi enkulu yeeprotheni zamamithachondrial ezinamandla, ezininzi zazo ezinokuthi zenzeke ngeendlela ezingekho ze-enzymatic, ziye zavela kwizifundo ze-proteomics (i-Dittenhafer-Reed et al., I2015; i-Rbert et al., I-2013 ; Shimazu et al., 2013). I-liysine deacetylases zisebenzisa i-zinc cofactor (umz., I-nucleocytosolic HDACs) okanye i-NAD + njenge-co-substrate (i-sirtuins, i-SIRTs) (i-Choudhary et al., I-2010; i-Menzies et al., I-2014). I-acetylproteome isebenza njengombini kunye nomphathi we-aletyl-CoA yamanzi, njengokuba izixhobo zomzimba kunye nezofuzo ziza kubangela ukuhlukahluka kwe-acetylation engekho-enzymatic (Weinert et al., 2016). Njengoko i-metabolites ye-intracellular isebenza njengabalawuli be-lysine ase-acetylation asele, kubalulekile ukuqwalasela indima yamalungu e-ketone, ubuninzi bawo bunamandla.

?OHB sisilungisi se-epigenetic ngokusebenzisa ubuncinci iindlela ezimbini. Ukunyuka kwe-?Amanqanaba e-OHB abangelwa ukuzila ukutya, ukuthintela i-caloric, ulawulo oluthe ngqo okanye ukuzivocavoca ixesha elide kuvusa inhibition ye-HDAC okanye i-histone acetyltransferase activation (Marosi et al., 2016; Sleiman et al., 2016) okanye uxinzelelo lwe-oxidative (Shimazu et al.), . ?I-OHB inhibition ye-HDAC2013 inokulawula i-physiology ye-metabolic physiology (uRando et al., 3). Ngokuzimeleyo, ?OHB ngokwayo iguqula ngokuthe ngqo iintsalela ze-histone lysine (Xie et al., 2016). Ukuzila ukutya ixesha elide, okanye i-steptozotocin-induced diabetic ketoacidosis yandise i-histone ?-hydroxybutyrylation. Nangona inani le-lysine ?-hydroxybutyrylation kunye neendawo ze-acetylation zazithelekiseka, i-stoichiometrically enkulu i-histone ?-hydroxybutyrylation kune-acetylation yabonwa. Ufuzo olwahlukileyo lwachatshazelwa yi-histone lysine ?-hydroxybutyrylation, ngokuchasene ne-acetylation okanye i-methylation, ebonisa imisebenzi eyahlukeneyo yeselula. Nokuba i-?-hydroxybutyrylation izenzekela okanye i-enzymatic akwaziwa, kodwa yandisa uluhlu lweendlela ngokusebenzisa imizimba yeketone echaphazela ngokuguquguqukayo ukukhutshelwa.

Iziganeko ezibalulekileyo zokuhlengahlengiswa kweeseli ngexesha lokuthintelwa kwekhalori kunye nokunciphisa izondlo zingaxutywa kwi-SIRT3- kunye ne-SIRT5-exhomekeke kwi-mitochondrial deacetylation kunye ne-desuccinylation, ngokulandelanayo, ukulawula iiprotheni ze-ketogenic kunye ne-ketolytic kwinqanaba le-post-translation kwisibindi kunye nezicubu ze-extrahepatic (i-Dittenha-Reed e-Reed. 2015; Hebert et al., 2013; Rardin et al., 2013; Shimazu et al., 2010). Nangona uthelekiso lwe-stoichiometric lweendawo ezithathiweyo aludibanisi ngokuthe ngqo kwiinguqu kwi-metabolic flux, i-acetylation ye-mitochondrial iguquguqukayo kwaye inokuqhutywa yi-acetyl-CoA yoxinaniso okanye i-mitochondrial pH, kunokuba i-enzymatic acetyltransferases (Wagner no-Payne, i-2013). Ukuba i-SIRT3 kunye ne-SIRT5 imodareyitha imisebenzi ye-ketone umzimba we-metabolizing enzymes iphakamisa umbuzo wendima ehambelanayo yee-ketones ekufakeni i-acetylproteome, i-succinylproteome, kunye nezinye iithagethi zeselula ezinamandla. Ewe, njengoko ukwahluka kwe-ketogenesis kubonakalisa ukugxila kwe-NAD +, ukuveliswa kwe-ketone kunye nobuninzi kunokulawula umsebenzi we-sirtuin, ngaloo ndlela kuphembelela amachibi e-acetyl-CoA/succinyl-CoA ewonke, i-acylproteome, kwaye ke i-mitochondrial kunye ne-cell physiology. ?-i-hydroxybutyrylation yeentsalela ze-enzyme ye-lysine inokongeza omnye umaleko kwi-reprogramming yeselula. Kwizicubu ze-extrahepatic, i-ketone body oxidation inokuvuselela utshintsho olufanayo kwi-cell homeostasis. Ngelixa i-compartmentation yamachibi e-acetyl-CoA ilawulwa kakhulu kwaye ilungelelanisa uluhlu olubanzi lweenguqu zeselula, ukukwazi kwemizimba ye-ketone ukubumba ngokuthe ngqo zombini i-mitochondrial kunye ne-cytoplasmic acetyl-CoA i-concentrations ifuna ukucaciswa (Chen et al., 2012; Corbet et al., 2016; Pougovkina et al., 2014; Schwer et al., 2009; Wellen noThompson, 2012). Ngenxa yokuba i-acetyl-CoA igxininisekile ilawulwa ngokuqinileyo, kwaye i-acetyl-CoA i-membrane impermeant, kubalulekile ukuqwalasela iindlela zomqhubi zokulungelelanisa i-acetyl-CoA homeostasis, kubandakanywa amazinga emveliso kunye ne-oxidation ye-terminal kumjikelo we-TCA, ukuguqulwa kwimizimba ye-ketone, i-mitochondrial. i-efflux nge-carnitine acetyltransferase (i-CrAT), okanye i-acetyl-CoA ukuthumela ngaphandle kwe-cytosol emva kokuguqulwa kwi-citrate kunye nokukhululwa nge-ATP citrate lyase (ACLY). Iindima eziphambili zezi ndlela zokugqibela kwi-cell acetylproteome kunye ne-homeostasis zifuna ukuqonda okufanayo kweendima ze-ketogenesis kunye ne-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 and Thompson, 2012). Ubuchwephesha obuguquguqukayo kwi-metabolomics kunye ne-acylproteomics ekusekweni kweemodeli eziguquguqukayo zofuzo ziya kufuneka ukuba zichaze iithagethi kunye neziphumo.

Iimpendulo ze-Anti-and Pro-Inflammatory Responses to Ketone Bodies

I-Ketosis kunye nemizimba ye-ketone imodareyitha ukuvuvukala kunye nokusebenza kweeseli zomzimba, kodwa iindlela ezahlukeneyo kunye nezingahambelaniyo ziye zacetywa. Ukunciphisa izondlo ixesha elide kunciphisa ukuvuvukala (Youm et al., 2015), kodwa i-ketosis engapheliyo yohlobo lwe-1 yeswekile yimeko ye-pro-inflammatory (Jain et al., 2002; Kanikarla-Marie noJain, 2015; Kurepa et al., 2012) ). Iindima ze-Mechanism-based signaling roles ze-?OHB ekudumbeni zivela ngenxa yokuba iiseli ezininzi ze-immune system, kuquka i-macrophages okanye i-monocytes, zivakalisa kakhulu i-GPR109A. Ngelixa i-?OHB isebenzisa impendulo echasene nokuvuvukala (Fu et al., 2014; Gambhir et al., 2012; Rahman et al., 2014; Youm et al., 2015), ukugxilwa okuphezulu kwemizimba ye-ketone, ngakumbi i-AcAc, qalisa impendulo ye-pro-inflammatory (uJain et al., 2002; Kanikarla-Marie noJain, 2015; Kurepa et al., 2012).

Iindima ezichasene nokuvuvukala kwe-GPR109A ligands kwi-atherosclerosis, ukukhuluphala, isifo sesibindi esivuthayo, isifo se-neurological, kunye nomhlaza ziye zahlaziywa (Graff et al., 2016). Inkcazo ye-GPR109A yongezwa kwiiseli ze-RPE zeemodeli zesifo sikashukela, izigulane zesifo seswekile (Gambhir et al., 2012), kunye ne-microglia ngexesha le-neurodegeneration (Fu et al., 2014). Iimpembelelo ezichasayo ze-?OHB ziphuculwe yi-GPR109A yokugqithisa kakhulu kwiiseli ze-RPE, kwaye ichithwe yi-pharmacological inhibition okanye i-genetic knockout ye-GPR109A (Gambhir et al., 2012). ?OHB kunye ne-nicotinic acid engaphandle (i-Taggart et al., 2005), zombini zinikela iziphumo ezichasayo kwi-TNF? okanye ukuvuvukala okubangelwa yi-LPS ngokunciphisa amanqanaba eprotheyini ye-pro-inflammatory (iNOS, COX-2), okanye i-cytokines efihliweyo (TNF?, IL-1?, IL-6, CCL2 / MCP-1), ngokuyinxalenye ngokuthintela i-NF -?B translocation (Fu et al., 2014; Gambhir et al., 2012). ?OHB inciphisa uxinzelelo lwe-ER kunye ne-NLRP3 inflammasome, isebenze impendulo yoxinzelelo lwe-antioxidative (Bae et al., 2016; Youm et al., 2015). Nangona kunjalo, kwi-neurodeergenerative inflammation, i-GPR109A-exhomekeke ?Ukukhuselwa kwe-OHB-mediated ayibandakanyi abalamli abavuthayo njenge-MAPK indlela yokubonisa indlela (umz., ERK, JNK, p38) (Fu et al., 2014), kodwa inokufuna i-PGD1 exhomekeke kwi-COX-2 imveliso (Rahman et al., 2014). Kuyathakazelisa ukuba i-macrophage GPR109A iyadingeka ukuba isebenzise umphumo we-neuroprotective kwimodeli ye-ischemic stroke (Rahman et al., 2014), kodwa ukukwazi kwe-?OHB ukuvimbela i-NLRP3 inflammasome kwi-bone macrophages ephuma kwi-macrophages yi-GPR109A ezimeleyo (Youm et al. ., 2015). Nangona uphando oluninzi ludibanisa? I-OHB kwimiphumo echasayo, i-? I-Anti- versus pro-inflammatory effects of ?OHB ke ngoko inokuxhomekeka kudidi lweeseli, ?OHB concentration, ixesha lokuba sesichengeni, kunye nobukho okanye ukungabikho kweemodyuli ezisebenzisanayo.

Ngokungafaniyo ne-?OHB, i-AcAc inokuvula umqondiso obonisa ukudumba. I-AcAc ephakamileyo, ngokukodwa nge-concentration ye-glucose ephezulu, iqinisa ukulimala kweeseli ze-endothelial ngokusebenzisa i-NADPH oxidase / i-oxidative stress dependent mechanism (Kanikarla-Marie noJain, 2015). Uxinzelelo oluphezulu lwe-AcAc kwintambo ye-umbilical yoomama abanesifo seswekile yadityaniswa nesantya esiphezulu se-protein oxidation kunye ne-MCP-1 yoxinaniso (Kurepa et al., 2012). I-AcAc ephezulu kwizigulane ezinesifo seswekile yayinxulunyaniswa ne-TNF? intetho (i-Jain et al., 2002), kunye ne-AcAc, kodwa hayi ., 1).

Iziganeko ze-Ketone ezixhomekeke kumzimba we-ketone zivame ukuqhutyelwa kuphela ngokugxininiswa komzimba we-ketone (> 5 mM), kwaye kwimeko yezifundo ezininzi ezidibanisa i-ketones kwi-pro- okanye i-anti-inflammatory effects, ngokusebenzisa iindlela ezingacacanga. Ukongezelela, ngenxa yemiphumo ephikisanayo ye-?OHB ngokumelene ne-AcAc ekudumbeni, kunye nokukwazi kwe-AcAc /? I-OHB ngokwemilinganiselo eyahluka-hlukeneyo, kunye nokwahluka koxinaniso olongezelekayo [umzekelo, (Saito et al., 2016)]. Ekugqibeleni, i-AcAc inokuthengwa ngokuthengisa kuphela njengetyuwa ye-lithium okanye njenge-ethyl ester efuna isiseko se-hydrolysis ngaphambi kokusetyenziswa. I-Lithium cation ngokuzimeleyo ibangela ukuhanjiswa kwe-signal cascades (Manji et al., 1995), kunye ne-AcAc anion i-labile. Okokugqibela, izifundo zisebenzisa i-racemic d/l-?OHB zinokubhidaniswa, njengoko kuphela i-d-?OHB stereoisomer inokudityaniswa kwi-AcAc, kodwa i-d-?OHB kunye ne-l-?OHB inomqondiso ngamnye nge-GPR109A, inhibit i-NLRP3 inflammasome, kwaye zisebenza njenge-lipogenic substrates.

Amathunjini e-Ketone, uxinzelelo lwe-Oxidative, kunye ne-neuroprotection

Uxinzelelo lwe-oxidative luchazwa njengemeko apho i-ROS ibonakaliswe ngokugqithisileyo, ngenxa yemveliso egqithisileyo kunye / okanye ukupheliswa kokuphazamiseka. I-Antioxidant kunye ne-oxidative yokunciphisa uxinzelelo lweendima zemizimba ye-ketone zichazwe ngokubanzi zombini kwi-vitro nakwi-vivo, ngakumbi kumxholo we-neuroprotection. Njengoko uninzi lwe-neurons lungenzi ngokufanelekileyo i-phosphates yamandla aphezulu ukusuka kwi-acids enamafutha-kodwa i-oxidize imizimba ye-ketone xa i-carbohydrates inqabile, iziphumo ze-neuroprotective zemizimba ye-ketone zibaluleke kakhulu (Cahill GF Jr, 2006; u-Edmond et al., 1987; Yang kunye nabanye, ngo-1987). Kwiimodeli zoxinzelelo lwe-oxidative, i-BDH1 induction kunye nokunyanzeliswa kwe-SCOT iphakamisa ukuba i-ketone body metabolism inokuphinda ihlelwe kwakhona ukuze igcine ukubonakaliswa kweeseli ezahlukeneyo, amandla e-redox, okanye iimfuno ze-metabolic (Nagao et al., 2016; Tieu et al., 2003).

Imizimba yeKetone inciphisa amabakala omonakalo weselula, ukulimala, ukufa kunye ne-apoptosis ephantsi kwi-neurons kunye ne-cardiomyocytes (iHaces et al., 2008; Maalouf et al., 2007; Nagao et al., 2016; Tieu et al., 2003). Iindlela eziceliweyo ziyahluka kwaye azisoloko zihambelana noxinaniso. Uxinzelelo lwe-millimolar ephantsi ye-(d okanye i-l)-?OHB ihlamba i-ROS (i-hydroxyl anion), ngelixa i-AcAc icoca iintlobo ezininzi ze-ROS, kodwa kuphela kugxininiso oludlula uluhlu lwe-physiological (IC50 20�67 mM) (Haces et al., 2008) . Ngokuchaseneyo, impembelelo enenzuzo phezu kwekhonkco lothutho lwe-electron's redox enokubakho yindlela eqhele ukunxulunyaniswa ne-d-?OHB. Ngelixa zonke imizimba emithathu ye-ketone (d/l-?OHB kunye ne-AcAc) yanciphisa ukufa kweeseli ze-neuronal kunye nokuqokelela kwe-ROS okubangelwa yi-chemical inhibition ye-glycolysis, kuphela i-d-?OHB kunye ne-AcAc ithintele ukuhla kwe-neuronal ATP. Ngokwahlukileyo, kwi-hypoglycemic kwimodeli ye-vivo, (d okanye i-l) -? ; Tieu et al., 2008). Izifundo ze-vivo zeempuku zondliwe ukutya kwe-ketogenic (i-2007% kcal fat kunye ne-2016% yeprotheni) ibonise ukuhluka kwe-neuroanatomical ye-antioxidant umthamo (Ziegler et al., 2009), apho utshintsho olunzulu lwabonwa kwi-hippocampus, ngokunyuka kwe-glutathione peroxidase kunye nenani lilonke. amandla antioxidant.

Ukutya kwe-Ketogenic, i-ketone esters (kwakhona ubone Ukusetyenziswa koNyango lokutya kwe-ketogenic kunye nemizimba ye-ketone yangaphandle), okanye ? isifo sikaParkinson (Tieu et al., 2014); inkqubo ye-nervous central ne-oxygen toxicity seizure (D'Agostino et al., 2003); i-epileptic spasms (Yum et al., 2013); i-encephalomyopathy ye-mitochondrial, i-lactic acidosis kunye ne-stroke-like (MELAS) i-episodes syndrome (uFrey et al., 2015) kunye nesifo se-Alzheimer (uCunnane noCrawford, i-2016; i-Yin et al., 2003). Ngokwahlukileyo, ingxelo yamva nje ibonise ubungqina be-histopathological yenkqubela phambili ye-neurodeergenerative ngokutya kwe-ketogenic kwimodeli yemouse ye-transgenic yokulungiswa kwe-DNA ye-mitochondrial engaqhelekanga, ngaphandle kokunyuka kwe-mitochondrial biogenesis kunye ne-antioxidant signatures (Lauritzen et al., 2016). Ezinye iingxelo eziphikisanayo zibonisa ukuba ukuvezwa kwimizimba ye-ketone ephezulu kubangela uxinzelelo lwe-oxidative. I-high ?I-OHB okanye i-AcAc doses eyenza i-nitric oxide secretion, i-lipid peroxidation, ukunciphisa ukubonakaliswa kwe-SOD, i-glutathione peroxidase kunye ne-catalase kwi-hepatocytes yethole, ngelixa i-hepatocytes ye-rat i-MAPK indlela yokungeniswa kweendlela yayibizwa ngokuba yi-AcAc kodwa kungekhona? ; Shi et al., 2016; Shi et al., 2004).

Kuthatyathwe kunye, iingxelo ezininzi zidibanisa? I-OHB ekunciphiseni uxinzelelo lwe-oxidative, njengoko ulawulo lwayo luvimbela i-ROS / imveliso ye-superoxide, ikhusela i-lipid peroxidation kunye ne-protein oxidation, inyusa amanqanaba eprotheni ye-antioxidant, kunye nokuphucula ukuphefumula kwe-mitochondrial kunye nokuveliswa kwe-ATP (Abdelmegeed et al., 2004; Haces et al., 2008; Jain et al., 1998; Jain et al., 2002; Kanikarla-Marie kunye noJain, 2015; Maalouf et al., 2007; Maalouf kunye noRho, 2008; Marosi et al., Tieu2016, 2003 et al., 2016; Yin et al., 2003; Ziegler et al., 2002). Ngelixa i-AcAc idityaniswe ngokuthe ngqo ngakumbi kune-?OHB kunye nokungeniswa koxinzelelo lwe-oxidative, ezi ziphumo azisoloko zichithwa ngokulula kwiimpendulo ezilindelekileyo zokuvuvukala (uJain et al., 2015; Kanikarla-Marie noJain, 2016; Kanikarla-Marie kunye UJain, ngo-2016). Ngaphezu koko, kubalulekile ukuqwalasela ukuba inzuzo ebonakalayo ye-antioxidative eyenziwa yi-pleiotropic ye-ketogenic yokutya ayinako ukudluliselwa yimizimba ye-ketone ngokwazo, kwaye i-neuroprotection enikezelwa yimizimba ye-ketone ayinakubangelwa ngokupheleleyo kuxinzelelo lwe-oxidative. Ngokomzekelo ngexesha lokunciphisa i-glucose, kwimodeli yokunciphisa i-glucose kwi-cortical neurons, i-? d-?OHB induces kwakhona i-canonical antioxidant proteins FOXO3a, SOD, MnSOD, kunye ne-catalase, ngokubonakalayo nge-HDAC inhibition (Nagao et al., 2016; Shimazu et al., 2013).

Izifo ezingenalo utywala (ii-NAFLD) kunye neCetone Body Metabolism

Ukutyeba okunxulunyaniswa ne-NAFLD kunye ne-nonalcoholic steatohepatitis (NASH) zezona zinto zibangela isifo sesibindi kumazwe aseNtshona (i-Rinella kunye ne-Sanyal, 2016), kunye nokusilela kwesibindi okubangelwa yi-NASH sesinye sezizathu eziqhelekileyo zokufakwa kwesibindi. Ngelixa ukugcinwa okungaphezulu kwe-triacylglycerols kwii-hepatocytes> i-5% yesisindo sesibindi (i-NAFL) iyodwa ayibangeli ukusebenza kwesibindi okuguqulwayo, ukuqhubela phambili kwi-NAFLD ebantwini kuhambelana nenkqubo ye-insulin yokumelana kunye nokwanda komngcipheko wohlobo lweswekile 2, kwaye kunokuba negalelo kwi-pathogenesis isifo sentliziyo kunye nesifo sezintso esinganyangekiyo (UFabbrini et al., 2009; UTargher et al., 2010; UTargher kunye noByrne, 2013). Iinkqubo ze-pathogenic ze-NAFLD kunye ne-NASH aziqondwa kakuhle kodwa zibandakanya ukungahambi kakuhle kwesifo se-hepatocyte metabolism, i-hepatocyte autophagy kunye noxinzelelo lwe-endoplasmic reticulum, ukusebenza kweeseli zomzimba, i-adipose ukudumba kwezicubu, kunye nabalamli abanoxinano lwenkqubo (UFabbrini et al., 2009; Masuoka kunye neChalasani, 2013 ; UTargher et al., 2010; UYang et al., 2010). Ukutshintshwa kwe-carbohydrate, lipid, kunye ne-amino acid metabolism kunye negalelo kukutyeba, isifo seswekile, kunye ne-NAFLD ebantwini nakwimodeli yezinto eziphilayo [ezihlaziyiweyo ku (UFarese et al., 2012; iLin kunye neAccili, 2011; INewgard, 2012; USamuel no UShulman, 2012; Ilanga kunye noLazaro, 2013)]. Ngelixa i-hepatocyte yokungaqhelekanga kwi-cytoplasmic lipid metabolism ibonwa rhoqo kwi-NAFLD (UFabbrini et al., 2010b), indima ye-mitochondrial metabolism, elawula ukulahlwa kwamafutha kwe-oxidative ayicacanga ncam kwi-NAFLD pathogenesis. Ukungaqheleki kwemetabolondrial metabolism kwenzeka kwaye kunegalelo kwi-NAFLD / NASH pathogenesis (IHyotylainen et al., 2016; Serviddio et al., 2011; Serviddio et al., 2008; Wei et al., 2008). Kukho ngokubanzi (Felig et al., 1974; Iozzo et al., 2010; Koliaki et al., 2015; Satapati et al., 2015; Satapati et al., 2012; Ilanga et al., 2011) kodwa ayifani ( UKoliaki noRoden, 2013; Perry et al., 2016; Rector et al., 2010) isivumelwano sokuba, ngaphambi kokuphuhliswa kwe-NASH ye-bona fide, i-hepatic mitochondrial oxidation, ngakumbi i-oxydation ye-fat, yongezwa ekutyebeni kakhulu, , kunye neNAFLD. Kusenokwenzeka ukuba njengoko i-NAFLD iqhubeka, amandla e-oxidative heterogenity, nditsho naphakathi kwemitochondria nganye, iyavela, kwaye ekugqibeleni umsebenzi we-oxidative uye ungasebenzi (UKoliaki et al., 2015; Ngqonyela et al., 2010; ISatapati et al., 2008; ISatapati okqhubekayo. ., 2012).

I-Ketogenesis isoloko isetyenziswa njenge-proxy ye-hepatic fat oxidation. Ukukhubazeka kwe-ketogenesis kuvela njengoko i-NAFLD iqhubela phambili kwiimodeli zezilwanyana, kwaye mhlawumbi kubantu. Ngeendlela ezingachazwanga ngokupheleleyo, i-hyperinsulinemia icinezela i-ketogenesis, enokuba negalelo kwi-hypoketonemia xa kuthelekiswa nolawulo oluthambileyo (Bergman et al., 2007; Bickerton et al., 2008; Satapati et al., 2012; Soeters et al., 2009; 2011; , 2005; Vice et al., 2015). Nangona kunjalo, ukukwazi ukujikeleza i-ketone body concentrations ukuqikelela i-NAFLD iphikisana (M'nnist et al., 2001; Sanyal et al., 2012). Iindlela eziqinileyo zobungakanani bemagnethi ye-resonance spectroscopic kwiimodeli zezilwanyana zibonakalise ukwanda kwereyithi ye-ketone yokunganyangeki kwe-insulin, kodwa amaxabiso anciphileyo abonakala ngoxhathiso oluqatha lwe-insulin (Satapati et al., 2010; Sunny et al., 2008). Kubantu abatyebe ngokugqithiseleyo abanesibindi esinamafutha, izinga le-ketogenic liqhelekileyo (Bickerton et al., 2011; Sunny et al., 4), kwaye ngoko, amazinga e-ketogenesis ayancipha ngokumalunga nokunyuka kwe-fatty acid load ngaphakathi kwe-hepatocytes. Ngenxa yoko, i-acetyl-CoA ephuma kwi-oxidation inokubhekiswa kwi-terminal oxidation kumjikelo we-TCA, ukwandisa i-terminal oxidation, i-phosphoenolpyruvate-driven gluconeogenesis nge-anaplerosis/cataplerosis, kunye noxinzelelo lwe-oxidative. I-Acetyl-CoA nayo inokuthi ihambe ngaphandle kwe-mitochondria njenge-citrate, i-precursor substrate ye-lipogenesis (Umfanekiso we-2015) (i-Satapati et al., 2012; Satapati et al., 2015; Solinas et al., 2012). Ngelixa i-ketogenesis iba yimpendulo encinci kwi-insulin okanye ukuzila ukutya ngokukhuluphala ixesha elide (i-Satapati et al., 1), iindlela ezisezantsi kunye neziphumo ezisezantsi zoku zihlala zingaqondwa ngokupheleleyo. Ubungqina bamva nje bubonisa ukuba i-mTORC2016 icinezela i-ketogenesis ngendlela enokuthi ibe phantsi kwe-insulin yokubonisa (Kucejova et al., 1), ehambelana nokuqwalaselwa kwe-mTORC2 inqanda i-PPAR?-mediated Hmgcs2010 induction (Sengupta et al., 2). kwakhona ubone ukuLawulwa kwe-HMGCS1 kunye ne-SCOT / OXCTXNUMX).

Ukuqwalaselwa kwangaphambili kwiqela lethu kubonisa imiphumo emibi ye-hepatic yokungaphumeleli kwe-ketogenic (Cotter et al., 2014). Ukuvavanya i-hypothesis ephazamisa i-ketogenesis, nakwi-carbohydrate-replete kwaye ngoko ke "non-ketogenic" ithi, igalelo kwi-metabolism ye-glucose engaqhelekanga kwaye ibangele i-steatohepatitis, senze imodeli yempuku yokungaphumeleli kwe-ketogenic ngokulawulwa kwe-oligonucleotides ye-antisense (ASO) ejoliswe kuyo. Hmgcs2. Ukulahleka kwe-HMGCS2 kwimicebe yabantu abadala ephantsi kwamafutha aphantsi kubangele i-hyperglycemia ethambileyo kwaye inyuse ngokuphawulekayo imveliso yamakhulu ee-metabolites ze-hepatic, i-suite ephakamisa ngamandla i-lipogenesis activation. Ukutya okunamafutha aphezulu kwiigundane kunye ne-ketogenesis eyaneleyo kubangele ukulimala okukhulu kwe-hepatocyte kunye nokuvuvukala. Ezi ziphumo zixhasa i-hypotheses ephakathi ukuba (i) i-ketogenesis ayiyona indlela yokuphuphuma kwe-passive kodwa kunokuba i-node eguquguqukayo kwi-hepatic kunye ne-homeostasis edibeneyo ye-physiological, kunye (ii) nolwandiso olulumkileyo lwe-ketogenic ukunciphisa i-NAFLD / NASH kunye ne-disordered hepatic glucose metabolism ifanele ukuphononongwa. .

Ngaba i-ketogenesis ephazamisekileyo inokuba negalelo njani kumonzakalo we-hepatic kunye nokuguqulwa kwe-glucose homeostasis? Ingqwalasela yokuqala kukuba ngaba umtyholi unqongophala kwe-ketogenic flux, okanye i-ketones ngokwabo. Ingxelo yakutshanje ibonisa ukuba imizimba ye-ketone inokunciphisa uxinzelelo lwe-oxidative olubangelwa ukulimala kwe-hepatic ekuphenduleni i-n-3 polyunsaturated fatty acids (Pawlak et al., 2015). Khumbula ukuba ngenxa yokungabikho kokubonakaliswa kwe-SCOT kwi-hepatocytes, imizimba ye-ketone ayinayo i-oxidized, kodwa inokuba negalelo kwi-lipogenesis, kwaye isebenze kwiindidi ezahlukeneyo zokubonisa ngokuzimeleyo kwi-oxidation yazo (kwakhona ubone i-Non-oxidative metabolic fates of ketone bodies and ?OHB as umlamli obonisa umqondiso). Kwakhona kunokwenzeka ukuba imizimba ye-ketone ephuma kwi-hepatocyte ingasebenza njengomqondiso kunye / okanye i-metabolite kwiintlobo zeeseli ezingabamelwane ngaphakathi kwe-hepatic acinus, kubandakanywa iiseli ze-stellate kunye ne-Kupffer cell macrophages. Ngelixa uncwadi olunyiniweyo olukhoyo lucebisa ukuba ii-macrophages azikwazi ukwenza i-oxidize imizimba ye-ketone, oku kulinganiswe kuphela kusetyenziswa iindlela zakudala, kwaye kuphela kwi-peritoneal macrophages (Newsholme et al., 1986; Newsholme et al., 1987), ebonisa ukuba ukuphinda- Uvavanyo lufanelekile lunikezwe ukubonakaliswa kwe-SCOT eninzi kwi-macrophages eyenziwe ngamathambo (Youm et al., 2015).

I-Hepatocyte ketogenic flux ingaba yi-cytoprotective. Nangona iindlela zobuncwane zingaxhomekekanga kwi-ketogenesis nganye, ukutya okuphantsi kwe-carbohydrate ketogenic kuye kwadibaniswa nokuphucula i-NAFLD (Browning et al., 2011; Foster et al., 2010; Kani et al., 2014; Schugar noCrawford, 2012) . Ukuqwalasela kwethu kubonisa ukuba i-hepatocyte ketogenesis inokuphendula kwaye ilawule i-TCA cycle flux, i-anaplerotic flux, i-phosphoenolpyruvate-derived gluconeogenesis (Cotter et al., 2014), kunye nokuguqulwa kwe-glycogen. I-Ketogenic impairment iqondisa i-acetyl-CoA yokwandisa i-TCA flux, esibindi idibaniswe nokunyuka kokulimala kwe-ROS (Satapati et al., 2015; Satapati et al., 2012); inyanzelisa ukuphambukiswa kwekhabhoni ibe ziintlobo zelipid ezidityanisiweyo ezinobungqina be-cytotoxic; kwaye inqanda i-NADH i-oxidation kwakhona kwi-NAD + (Cotter et al., 2014) (Umfanekiso 4). Kuthatyathwe kunye, iimvavanyo zexesha elizayo ziyafuneka ukujongana neendlela apho ukusilela kwe-ketogenic kunokuthi kube yi-maladaptive, igalelo kwi-hyperglycemia, ikhuphe i-steatohepatitis, nokuba ezi ndlela zisebenza kwi-NAFLD/NASH yabantu. Njengoko ubungqina be-epidemiological bubonisa ukukhubazeka kwe-ketogenesis ngexesha lokuqhubeka kwe-steatohepatitis (Embade et al., 2016; Marinou et al., 2011; Mnist et al., 2015; Pramfalk et al., 2015; Safaei 2016, unyango olwandisa i-ketogenesis ye-hepatic inobungqina obunobuncwane (i-Degirolamo et al., 2016; Honda et al., 2016).

Iimpawu zeCetone kunye nokungaphumeleli kwentliziyo (HF)

Ngesantya semetabolism esingaphezulu kwe-400 kcal/kg/ngosuku, kunye nenguquko ye-6�35 kg ye-ATP/ngosuku, intliziyo lilungu elineyona nkcitho iphezulu yamandla kunye nemfuno ene-oxidative (Ashrafian et al., 2007; Wang et al., 2010b). Uninzi lwenguqu yamandla e-myocardial ihlala ngaphakathi kwe-mitochondria, kwaye i-70% yolu nikezelo lusuka kwi-FAO. Intliziyo i-omnivorous kwaye ibhetyebhetye phantsi kweemeko eziqhelekileyo, kodwa intliziyo ehlaziya i-pathologically (umzekelo, ngenxa ye-hypertension okanye i-myocardial infarction) kunye nentliziyo yesifo seswekile nganye iyancipha i-metabolically inflexible (Balasse kunye noFery, 1989; BING, 1954; Fukao et al., 2004) ; Lopaschuk et al., 2010; Taegtmeyer et al., 1980; Taegtmeyer et al., 2002; Young et al., 2002). Enyanisweni, ukungahambi kakuhle kwemfuzo ye-cardiac fuel metabolism kwiimodeli zemouse kuvusa i-cardiomyopathy (uCarley et al., 2014; Neubauer, 2007). Ngaphantsi kweemeko ze-physiological hearts eziqhelekileyo zikhupha imizimba ye-ketone ngokulingana nokuhanjiswa kwazo, ngeendleko ze-fatty acid kunye ne-glucose oxidation, kwaye i-myocardium yeyona nto iphezulu yomthengi we-ketone yomzimba ngeyunithi yobunzima (BING, 1954; Crawford et al., 2009; GARLAND et al. ., 1962; Hasselbaink et al., 2003; Jeffrey et al., 1995; Pelletier et al., 2007; Tardif et al., 2001; Yan et al., 2009). Xa kuthelekiswa ne-oxidation ye-asidi enamafutha, imizimba ye-ketone isebenza ngamandla, inika amandla amaninzi akhoyo kwi-ATP synthesis nge-molecule ye-oksijini etyalwe (i-P / O ratio) (Kashiwaya et al., 2010; Sato et al., 1995; Veech, 2004) . I-Ketone body oxidation iphinda ivelise amandla angaphezulu kunokuba i-FAO, igcina i-ubiquinone oxidized, ephakamisa i-redox span kwikhonkco lokuthutha i-electron kwaye yenza amandla amaninzi afumaneke ukuze enze i-ATP (Sato et al., 1995; Veech, 2004). I-oxidation yemizimba ye-ketone inokunciphisa imveliso ye-ROS, kwaye ngoko ke uxinzelelo lwe-oxidative (Veech, 2004).

Izifundo zokuqala nokungenelela kunye nokuhlola okubonisa ukubonisisa zibonisa indima enokuyilungisa yamalungu e-ketone entliziyweni. Kwimizamo yokuzama ukutshatyalaliswa kwe-ischemia / i-reperfusion, izidumbu ze-ketone ezithe zenziwa yimiphumo ye-cardioprotective (Al-Zaid et al., 2007; i-Wang et al., I-2008), mhlawumbi ngenxa yokwanda kwe-mitochondrial in intliziyo okanye ukulawulwa kwe-phosphorylation ebalulekileyo abalamlamli (uSorek et al., 2012; Zou et al., 2002). Uphando olutshanje lubonisa ukuba ukusetyenziswa komzimba we-ketone kunyuke ekuphelelweni kweentlanzi (Aubert et al., 2016) kunye nabantu (Bedi et al., 2016), ukuxhasa ukubonwa kwangaphambili kubantu (BING, 1954; Fukao et al., 2000; Janardhan et al., 2011; Longo et al., 2004; Rudolph kunye neSchinz, 1973; iTildon kunye neConblath, i-1972). Ukwandiswa kwamanani emzimbeni we-ketone kunyuselwa kwintsholongwane yokukhubazeka kwentliziyo, ngokubhekiselele ekuzaliseni izixinzelelo, ukuqwalaselwa okubalulekileyo kunye nokubaluleka kwayo (Kupari et al., 1995; Lommi et al., 1996; Lommi et al., 1997; Neely et al ., I-1972), kodwa iigundane ezineenkcukacha ze-SCOT ezingabonakaliyo kwi-cardiomyocytes zibonisa ukulungiswa kwe-ventricular ventricular kunye ne-ROS zisayineli ekuphenduleni ukunyanzeliswa kwengcinezelo yokuxinzelela ingozi (Schugar et al., 2014).

Ukuqwalaselwa okwangoku okwangoku kukhangeleka kwindlela yesifo sikashukela kuye kwabonisa ukuba unxibelelwano olukhoyo phakathi kwe-myocardial ketone metabolism kunye ne-pathological ventricular remodeling (i-Fig. 5). Inhibition ye-renal proximal nebular tubular sodium / i-glucose co-transporter I-2 (SGLT2i) yandisa ukujikeleza komzimba we-ketone kubantu (Ferrannini et al., 2016a; Inagaki et al., 2015) kunye namagundane (Suzuki et al., 2014) ngokunyuka i-hepatic ketogenesis (iFerrannini et al., i-2014; i-Ferrannini et al., i-2016a; i-Katz kunye ne-Leiter, i-2015; i-Mudaliar et al., i-2015). Ngokukrakra, ubuncinane enye yee-arhente zanciphisa izibhedlele ze-HF (umz., Njengoko kuboniswe nguvavanyo lwe-EMPA-REG OUTCOME), kunye nokufelwa komzimba (Fitchett et al., 2016; Sonesson et al., 2016; Wu et al., 2016a : Zinman et al., 2015). Nangona umqhubi weendlela ezixhamlayo kwiziphumo ze-HF ezixhunyiwe kwi-SGLT2i zihlala zixubushe ngokuxubusha, inzuzo yokuphila isenokuthi iyenze i-ketosis kodwa ibuye iphumelele ekuthini isisindo, uxinzelelo lwegazi, i-glucose kunye namazinga e-uric acid, ukuqina kobunzima, inkqubo ye-nervous sympathetic, osmotic i-diuresis / umthamo we-plasm wehlisiwe, kunye ne-hematocrit eyanda (uRaz noCahn, i-2016; i-Vallon ne-Thomson, i-2016). Kuthatyathwa ndawonye, ​​ingcamango yokuba ukhenkethemia yokwandisa i-ketonemia kwii-HF izigulane, okanye abo basemngciphekweni omkhulu wokuhlakulela i-HF, ihlala ingquzulwano kodwa iphantsi kophando olusebenzayo kwizifundo zangaphambi kweklinikhi kunye neklinikhi (uFranran et al., 2016b; Kolwicz et al., 2016; Lopaschuk kunye neVerma, 2016; Mudaliar et al., 2016; iTeegtmeyer, 2016).

Amathambo e-Ketone kwi-Biology Cancer

Ukuqhagamshelana phakathi kweempawu ze-ketone kunye nomhlaza kukhula ngokukhawuleza, kodwa izifundo kwizifundo zezilwanyana kunye nabantu ziye zaveza izigqibo ezihlukahlukeneyo. Ngenxa yokuba i-ketone metabolism inamandla kunye nesimo sezondlo esiphendulayo, siyayilinganisa ukuqhubela phambili ukuxhamla kwi-biological kunye nomhlaza ngenxa yezinto ezinokuthathwa ngokuchanekileyo. Iiseli zomhlaza zingaphantsi kwe-reprogramming reprogramming ukwenzela ukuba kugcinwe ukukhula kweseli ngokukhawuleza nokukhula (iDeNicola kunye noCanley, i-2015; i-Pavlova kunye no-Thompson, i-2016). I-classic yaseWarburg eyenziwa ngumhlaza wesifo se-metabolism ibangelwa yinxaxheba ebalulekileyo ye-glycolysis kunye ne-lactic acid fermentation ukudlulisela amandla kwaye ihlawulise ukuxhomekeka okuphantsi kwe-phosphorylation ye-oxidative kunye nokuphefumula kwe-mitochondrial (De Feyter et al., 2016; Grabacka et al., 2016; Kang et al., 2015; Poff et al., 2014; Shukla et al., 2014). I-glucose carbon ilawulwa ngokuglycolysis, i-pentose phosphate pathway, kunye ne-lipogenesis, ezidibeneyo zibonelela ngezixhobo ezifunekayo ukwenyuka kwe-tumor biomass (i-Grabacka et al., I-2016; i-Shukla et al., I-2014; i-Yoshii et al., I-2015). Ukutshintshwa kweeseli zomhlaza kwi-glucose inyanzeliso kwenzeka ngokukwazi ukusebenzisa izixhobo zamanye amafutha, kuquka i-acetate, glutamine, kunye ne-aspartate (Jaworski et al., 2016; Sullivan et al., 2015). Ngokomzekelo, ukufikelela okuvumelekileyo kwi-pyruvate kubonisa amandla omhlaza weseli ukuguqula i-glutamine kwi-acetyl-CoA nge-carboxylation, ukugcina iimfuno zombini kunye ne-anabolic (uYang et al., 2014). Ukutshintshisiswa kokutshintshwa kweeseli zomhlaza kukusetyenziswa kwe-acetate njengamafutha (i-Comerford et al., I-2014; i-Jaworski et al., I-2016; i-Mashimo et al., I-2014; i-Wright ne-Simone, i- 2016; i-Yoshii et al., I-2015). I-Acetate iphinde ibe yintsika ye-lipogenesis, eyona nto ibaluleke kakhulu kwi-cell proliferation, kwaye inzuzo yalo mzila we-lipogenic ihambelana nesigulo esinesigxina sokusinda kunye nomthwalo omkhulu we-tumor (i-Comerford et al., I-2014; i-Mashimo et al., I-2014; i-Yoshii et al ., 2015).

Iiseli ezingezonomhlaza zitshintsha ngokulula umthombo wazo wamandla ukusuka kwi-glucose ukuya kwimizimba ye-ketone ngexesha lokungabikho kweglucose. Le plasticity inokuthi iguquguquke ngakumbi phakathi kweentlobo zeeseli zomhlaza, kodwa kwi-vivo efakwe kwi-brain tumors oxidized [2,4-13C2] -? �Ukubuyisela umva isiphumo se-Warburg� okanye �iimodeli ezimbini ze-tumor metabolism� ziqikelela ukuba iiseli zomhlaza zibangela ?Imveliso ye-OHB kwi-fibroblasts ekufutshane, ibonelela ngeemfuno zamandla zeseli yethumba (Bonuccelli et al., 2016; Martinez-Outschoorn et al., 2010) . Kwisibindi, utshintsho kwi-hepatocytes ukusuka kwi-ketogenesis ukuya kwi-ketone oxidation kwi-hepatocellular carcinoma (i-hepatoma) iiseli zihambelana nokusebenza kwe-BDH2012 kunye nemisebenzi ye-SCOT ebonwa kwimigca yeseli ye-hepatoma (Zhang et al., 1). Enyanisweni, iiseli ze-hepatoma zibonisa i-OXCT1989 kunye ne-BDH1 kunye ne-oxidize ketones, kodwa kuphela xa i-serum ilambile (Huang et al., 1). Kungenjalo, kuye kwacetywa i-tumor cell ketogenesis. Ukutshintsha okunamandla kwi-ketogenic gene expression kuboniswa ngexesha lokuguqulwa komhlaza we-colonic epithelium, uhlobo lweseli oluhlala lubonisa i-HMGCS2016, kwaye ingxelo yakutshanje iphakamisa ukuba i-HMGCS2 ingaba ngumqondiso we-prognosis ye-prognosis embi kwi-colorectal kunye ne-squamous cell carcinomas (Camarero et al., 2; Chen et al., 2006). Ingaba lo mbutho ufuna okanye ubandakanya i-ketogenesis, okanye umsebenzi wokukhanya kwenyanga we-HMGCS2016, uhlala uzimisele. Ngokuchaseneyo, kuyabonakala ?Imveliso ye-OHB ngemelanoma kunye neeseli ze-glioblastoma, ezivuselelwe yi-PPAR? I-agonist fenofibrate, yayinxulumene nokubanjwa kokukhula (Grabacka et al., 2). Uphononongo olongezelelweyo luyafuneka ukuba lubonise iindima ze-HMGCS2016 / SCOT expression, i-ketogenesis, kunye ne-ketone oxidation kwiiseli zomhlaza.

Ngaphandle kwendawo ye-fuel metabolism, ii-ketones zisandula ukubandakanyeka kwibhayoloji yeseli yomhlaza ngendlela yokubonisa. Uhlalutyo lwe-BRAF-V600E + i-melanoma ibonise i-OCT1-exhomekeke kwi-HMGCL exhomekeke kwi-oncogenic ye-BRAF exhomekeke kwindlela (Kang et al., 2015). Ukwandiswa kwe-HMGCL kwanxulunyaniswa noxinzelelo oluphezulu lwe-AcAc yeselula, eyathi yaphucula ukusebenzisana kwe-BRAFV600E-MEK1, ikhulisa umqondiso we-MEK-ERK kwi-feed-forward loop eqhuba ukwanda kwe-tumor cell kunye nokukhula. Olu qwalaselo luphakamisa umbuzo othakazelisayo we-extrahepatic ketogenesis enokuthi emva koko ixhase indlela yokubonisa (kwakhona ubone ?OHB njengomlamli womqondiso kunye neeNgxaki kwi-ketogenesis ye-extrahepatic). Kwakhona kubalulekile ukuqwalasela iziphumo ezizimeleyo ze-AcAc, d-?OHB, kunye ne-l-?OHB kwi-metabolism yomhlaza, kwaye xa uqwalasela i-HMGCL, i-leucine catabolism inokuthi iphazamiseke.

Imiphumo yokutya kwe-ketogenic (kwakhona jonga Ukusetyenziswa koNyango lokutya kwe-ketogenic kunye nemizimba ye-ketone yangaphandle) kwiimodeli zezilwanyana ezinomhlaza ziyahluka (De Feyter et al., 2016; Klement et al., 2016; Meidenbauer et al., 2015; Poff et al., 2014; Klement et al., 2011; Meidenbauer et al., 2014; Poff et al. ., 2016; Seyfried et al., 2016; Shukla et al., 2016). Ngelixa imibutho ye-epidemiological phakathi kokutyeba, umhlaza, kunye nokutya kwe-ketogenic kuxoxwa ngayo (Liskiewicz et al., 2016; Wright noSimone, 81), uhlalutyo lwe-meta olusebenzisa ukutya kwe-ketogenic kwimodeli yezilwanyana nakwizifundo zabantu lucebise impembelelo ephilileyo ekusindeni, kunye inzuzo enokuthi idibaniswe nobukhulu be-ketosis, ixesha lokuqalisa ukutya, kunye nendawo ye-tumor (Klement et al., 18; Woolf et al., 1). Unyango lweeseli zomhlaza we-pancreatic kunye nemizimba ye-ketone (d-?OHB okanye i-AcAc) inqanda ukukhula, ukwanda kunye ne-glycolysis, kunye nokutya kwe-ketogenic (i-2014% kcal fat, i-2014% yeprotheni, i-91% ye-carbohydrate) iyancipha kwi-vivo tumor weight, i-glycemia, kunye ukwanda kwemisipha kunye nobunzima bomzimba kwizilwanyana ezinomhlaza wokufakelwa (Shukla et al., 9). Iziphumo ezifanayo zabonwa kusetyenziswa imodeli yeseli ye-metastatic glioblastoma kwiigundane ezifumene i-ketone supplementation ekudleni (Poff et al., 2016). Ngokuchasene noko, ukutya kwe-ketogenic (i-2015% kcal fat, i-XNUMX% yeprotheyini) yanda ukujikeleza ?I-concentration ye-OHB kunye ne-glycemia eyanciphayo kodwa ayinayo impembelelo kwi-tumor volume okanye ubude bokuphila kwiigundane ezithwala i-glioma (De Feyter et al., XNUMX). Isalathisi se-glucose ketone sicetywayo njengesalathisi seklinikhi esiphucula ukulawulwa kwe-metabolic ye-ketogenic-induced brain cancer therapy kubantu kunye neegundane (Meidenbauer et al., XNUMX). Ithatyathwe kunye, iindima ze-ketone body metabolism kunye nemizimba ye-ketone kwibhayoloji yomhlaza iyathandeka kuba nganye ibeka iinketho zonyango ezithathekayo, kodwa imiba esisiseko isacaciswa, kunye neempembelelo ezicacileyo ezivela kwi-matrix yezinto eziguquguqukayo, kubandakanywa (i) umahluko phakathi kwe-ketone yangaphandle. imizimba echasene nokutya kwe-ketogenic, (ii) uhlobo lweseli yomhlaza, i-polymorphisms ye-genomic, ibakala, kunye nenqanaba; kunye (iii) nexesha kunye nobude bokuchanabeka kwi-ketotic state.

I-Ketogenesis yenziwe ngamalungu e-ketone ngokuphuhla kwama-acids acids kunye ne-ketogenic amino acid. Le nkqubo ye-biochemical inikeza amandla kumalungu athile, ngokukodwa ingqondo, phantsi kweemeko zokuzila ukutya njengendlela yokuphendula ukungabi khona kwegazi kwi-glucose. Izidumbu ze-ketone ziveliswa ikakhulu kwi-mitochondria yeselintshi yesibindi. Nangona ezinye iiseli ziyakwazi ukwenza i-ketogenesis, azinako ukwenza ngokufanelekileyo njengeseli zesibindi. Ngenxa yokuba i-ketogenesis ivela kwimitochondria, iinkqubo zayo zilawulwa ngokuzimela. UDkt Alex Jimenez DC, i-CCST Insight

Ukusetyenziswa kwezifo zeTetogenic Diet kunye namaBhunga aKonone aqhelekileyo

Ukusetyenziswa kwezidlo ze-ketogenic kunye nemizimba ye-ketone njengezixhobo zonyango ziye zavela nakwiimeko ezingenalo umhlaza ezibandakanya ukukhuluphala kunye ne-NAFLD / NASH (Browning et al., 2011; Foster et al., 2010; Schugar and Crawford, 2012); ukungaphumeleli kwentliziyo (Huynh, 2016; Kolwicz et al., 2016; Taegtmeyer, 2016); isifo se-neurological and neurodegenerative (uMartin et al., 2016; McNally kunye noHartman, 2012; Rho, 2015; Rogawski et al., 2016; Yang and Cheng, 2010; Yao et al., 2011); iimpazamo ezizalwayo zemetabolism (Scholl-B�rgi et al, 2015); kunye nokusebenza komthambo (Cox et al., 2016). Ukusebenza kokutya kwe-ketogenic kuye kwaxatyiswa ngakumbi kunyango lokuxhuzula, ngakumbi kwizigulana ezinganyangekiyo ngamachiza. Uninzi lwezifundo ziye zavavanya ukutya kwe-ketogenic kwizigulana zabantwana, kwaye zityhila ukuya kuthi ga kwi- ~ 50% yokunciphisa imvamisa yokubamba emva kweenyanga ze-3, ngokusebenza okuphuculweyo kwii-syndromes ezikhethiweyo (Wu et al., 2016b). Amava anqongophele ngakumbi kwisifo sokuxhuzula kwabantu abadala, kodwa ukuncitshiswa okufanayo kubonakala, kunye nempendulo engcono kwizigulana zokuxhuzula eziqhelekileyo (Nei et al., 2014). Iindlela ezingaphantsi kwe-anti-convulsant zihlala zingacacanga, nangona ii-hypotheses ezithunyelweyo ziquka ukunciphisa ukusetyenziswa kwe-glucose / glycolysis, i-reprogrammed glutamate transport, impembelelo engathanga ngqo kwi-ATP-sensitive potassium channel okanye i-adenosine A1 receptor, ukuguqulwa kwenkcazo ye-sodium ye-isoform, okanye imiphumo kwi-hormone ejikelezayo kuquka i-leptin. Lambrechts et al., 2016; Lin et al., 2017; Lutas noYellen, 2013). Kuhlala kungacacanga ukuba isiphumo sokuchasana nokuxhuzula sibangelwa ikakhulu kwimizimba ye-ketone, okanye ngenxa yemiphumo ye-cascade ye-metabolic yokutya okuphantsi kwe-carbohydrate. Nangona kunjalo, i-ketone esters (jonga ngezantsi) ibonakala iphakamisa umda wokubamba kwiimodeli zezilwanyana zokuhlutha okucaphukisayo (Ciarlone et al., 2016; D'Agostino et al., 2013; Viggiano et al., 2015).

I-Atkins-style kunye ne-ketogenic, i-low-carbohydrates diet zidlalwa njengento engathandekiyo, kwaye ingabangela ukumbumba, i-hyperuricemia, i-hypocalcemia, i-hypomagnesemia, ibangela i-nephrolithiasis, i-ketoacidosis, ibangele i-hyperglycemia, kwaye iphakame i-cholesterol kunye namafutha ase-fatty acid (Bisschop et al., 2001 ; IKossoff kunye neHartman, i-2012; i-Kwiterovich et al., I-2003; i-Suzuki et al., I-2002). Ngenxa yezi zizathu, ukubambelela kwexesha elide kubangela iingxaki. Izifundo zogqithiso zixhaphaza ngokubanzi ukusabalalisa ngokubanzi (i-94% kcal fat, i-1% kcal carbohydrate, i-5% kcal protein, i-Bio-Serv F3666), eyenza i-ketosis enamandla. Nangona kunjalo, ukwandisa umxholo weprotheni, nokuba i-10% kcal iyanciphisa kakhulu i-ketosis, kwaye i-5% kcal protein restriction ibangela ukuphazamiseka kwemiphumo ye-metabolic and physiological. Ukuqulunqwa kwesondlo kuphelile, enye intsingiselo echaphazela ukulimala kwesibindi, kunye ne-ketogenesis (Garbow et al., 2011; Jornayvaz et al., 2010; i-Kennedy et al., 2007; i-2013; i-Schugar kunye al., 2013). Iziphumo zokusetyenziswa kwexesha elide kwizidlo ze-ketogenic kwiimicebe zihlala zingachazwanga ngokucacileyo, kodwa uphando olutshanje kwiimicebe lubonakalisile ukusinda okuqhelekileyo kunye nokungabikho kwezimbonakaliso zokulimala kwesibindi kwiimfucu kwizidlo ze-ketogen ngaphezu kobomi babo, nangona i-amino acid metabolism, inkcitho yamandla kunye nokubonakaliswa kwe-insulin zachazwa ngokukhawuleza (Douris et al., 2015).

Iinkqubo zokwandisa i-ketosis ngeendlela ezingezinye iindlela zokutya zetokenjini ziquka ukusetyenziswa kwezinto zokugcoba umzimba ze-ketone. Ukulawulwa kweempawu ze-ketone ezingenakukwazi ukudala isimo semvelo esingafani naso kwi-physiology eqhelekileyo, kuba ukujikeleza i-glucose kunye namaqondo e-insulin aqhelekileyo, ngelixa iiseli zingasindisa i-glucose ukusetyenziswa kunye nokusetyenziswa. Imizimba yeKetone ngokwazo inobomi obufutshane obufutshane, kwaye ukungeniswa okanye ukufakwa kwesodium ?OHB ityuwa ukufezekisa i-ketosis yonyango ixhokonxa umthwalo wesodium engathandekiyo. I-R/S-1,3-butanediol yi-dialcohol engeyona inetyhefu ekhawuleza i-oxidized kwisibindi ukuze ivelise i-d/l-?OHB (Desrochers et al., 1992). Kwimixholo yovavanyo eyahlukeneyo, eli thamo lilawulwa yonke imihla kwiimpuku okanye iimpuku kangangeeveki ezisixhenxe, inika ukujikeleza ?OHB yoxinaniso ukuya kuthi ga kwi-5 mM ngaphakathi kwe-2 h yolawulo, ezinzile ubuncinane i-3h eyongezelelweyo (D') Agostino et al., 2013). Ukuncitshiswa okukodwa kokutya okuye kwabonwa kwiigorantshi zanikwa uR / S-1,3-butanediol (Umchweli kunye neGrossman, 1983). Ukongezelela, ezintathu zeekhemikhali ze-ketone esters (KEs), (i) i-monoester ye-R-1,3-butanediol kunye ne-d-?OHB (R-3-hydroxybutyl R-?OHB); (ii) i-glyceryl-tris-?OHB; kunye (iii) ne-R, S-1,3-butanediol acetoacetate diester, nayo ifundwe ngokubanzi (Brunengraber, 1997; Clarke et al., 2012a; Clarke et al., 2012b; Desrochers et al., 1995a; Desrochers et al., 1995a; Clarke et al., 2010b; Desrochers et al., XNUMXa; Desrochers et al. ., XNUMXb; Kashiwaya et al., XNUMX). I-advanteji yendalo yangaphambili kukuba ii-moles ezi-2 ze-physiological d-?OHB ziveliswa nge-mole ye-KE, kulandela i-esterase hydrolysis emathunjini okanye esibindini. Ukhuseleko, i-pharmacokinetics, kunye nokunyamezela kuye kwafundiswa ngokubanzi kubantu abasebenzisa i-R-3-hydroxybutyl R-? 714a; Cox et al., 6; Kemper et al., 2012; Shivva et al., 2016). Kwiingcongolo, oku ke kunciphisa i-caloric intake kunye ne-plasma ye-cholesterol iyonke, ikhuthaza i-brown adipose tissue, kwaye iphucula ukuxhathisa kwe-insulin (i-Kashiwaya et al., I-2010; i-Kemper et al., I-2015; i-Veech, i-2013). Iziphumo zakutshanje zibonisa ukuba ngexesha lokuzivocavoca kubadlali abaqeqeshiweyo, i-R-3-hydroxybutyl R-?OHB iyancipha i-skeletal muscle glycolysis kunye ne-plasma lactate concentrations, i-intramuscular triacylglycerol oxidation, kunye nokugcinwa kwe-muscle glycogen content, nangona xa i-carbohydrate edibeneyo ivuselela ukukhuselwa kwe-insulin. Cox et al., 2016). Ukuphuhliswa okuqhubekayo kwezi ziphumo ezikhangayo kuyadingeka, kuba ukuphucula ukunyamezela ukuqhuba ukusebenza kwakuqhutywe kakhulu yimpendulo enamandla kwi-KE kwizifundo ze-2 / 8. Nangona kunjalo, ezi ziphumo zixhasa ukufundiswa kweklasi ezibonisa ukhetho lwe-ketone oxidation ngaphezu kwamanye amacwecwe (GARLAND et al., 1962; Hasselbaink et al., 2003; Stanley et al., 2003; Valente-Silva et al., 2015), kubandakanywa ngexesha lokuzivocavoca, kwaye abadlali abaqeqeshiwe banokubongwa ukuba basebenzise ietone (Johnson et al., 1969a; uJohnson noWalton, 1972; Winder et al., 1974; Winder et al., 1975). Ekugqibeleni, iindlela ezinokuxhasa ukuqhuba umsebenzi ophuculweyo emva kokudla okulinganayo kwe-caloric (ukusabalaliswa ngokwahlukileyo phakathi kwama-macronutrients) kunye nokulingana kwamazinga okusetyenziswa kwe-oksijini kuya kuhlala kuchongwa.

Ngethuba elizayo

Yakuba ibekwe ibala kakhulu njengendlela ephuphumayo ekwaziyo ukuqokelela ukukhutshwa okuyityhefu okuphuma ekutshisweni kwamafutha kwiindawo ezithintelweyo zecarbohydrate (i-�ketotoxic� paradigm), uqwalaselo lwakutsha nje luxhasa uluvo lokuba i-ketone body metabolism isebenza iindima eziluncedo nakwimimandla enecarbohydrates, ivula i-ketohormetic. � ingcamango. Ngelixa iindlela ezilula zokondla kunye ne-pharmacological zokulawula i-ketone metabolism zenza ukuba kube yinjongo ekhangayo yonyango, i-aggressive ibekwe kodwa iimvavanyo ezinobulumko zihlala kuzo zombini iilebhu zophando ezisisiseko kunye nokuguqulela. Iimfuno ezingafezekanga ziye zavela kwimimandla yokuchaza indima ye-leveraging ketone metabolism kwintliziyo, ukukhuluphala, i-NAFLD / NASH, uhlobo lwe-2 yeswekile, kunye nomhlaza. Umda kunye nefuthe leendima 'ezingezo-canonical' zomqondiso wemizimba ye-ketone, kubandakanywa nolawulo lwee-PTM ezinokuthi zibuyele emva nangaphambili kwiindlela zemetabolism kunye nezibonakaliso, zifuna uphononongo olunzulu. Ekugqibeleni, i-ketogenesis ye-extrahepatic inokuvula i-paracrine enomdla kunye neendlela zokubonisa i-autocrine kunye namathuba okuchaphazela i-co-metabolism ngaphakathi kwenkqubo ye-nervous kunye ne-tumor ukuphumeza iziphelo zonyango.

Imibulelo

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

Imihlathi

Ncbi.nlm.nih.gov

Ukuqukumbela, imizimba ye-ketone idalwe sisibindi ukuze isetyenziswe njengomthombo wamandla xa kungekho glucose eyaneleyo efumanekayo kumzimba womntu. I-Ketogenesis yenzeka xa kukho amanqanaba eglucose ephantsi egazini, ngakumbi emva kokuba ezinye iivenkile ze-carbohydrate zeselula ziphelile. Injongo yale nqaku ingentla yayikuxoxa ngeendima ezininzi-dimensional zemizimba ye-ketone kwi-fuel metabolism, ukubonakaliswa, kunye nonyango. Ubungakanani bolwazi lwethu lukhawulelwe kwi-chiropractic kunye nemiba yempilo yomgogodla. Ukuxoxa ngalo mbandela, nceda uzive ukhululekile ukubuza uGqr. Jimenez okanye uqhagamshelane nathi apha915-850-0900 .

Ikhutshwe nguDkt. Alex Jimenez

Isingqinisiso sivela kwi: Ncbi.nlm.nih.gov/pmc/articles/PMC5313038/

Ingxoxo yesihloko esongezelelweyo: cBuhlungu obuBuhlungu

Umqolo obuhlunguSesinye sezona zinto zixhaphakileyo zokukhubazeka kunye neentsuku eziphosiweyo emsebenzini kwihlabathi liphela. Iimpawu ezibuhlungu zangasemva kwisizathu sesibini esiqhelekileyo sokutyelelwa kweofisi kagqirha, ngaphezulu kwenani losulelo oluphezulu lokuphefumla. Ngokumalunga neepesenti ezingama-80 zabemi baya kuba neentlungu zentlungu emva kanye ebomini babo. Umqolo sisakhiwo esintsonkothileyo esenziwe ngamathambo, amalungu, iigaments, kunye nezihlunu, phakathi kwezinye izicwili ezithambileyo. Ukwenzakala kunye / okanye iimeko ezixhonyiweyo, ezinje ngedisni, ekugqibeleni inokukhokelela kwiimpawu zentlungu emva. Ukulimala kwezemidlalo okanye ukulimala kwengozi yemoto kudla ngokuba yimbangela eqhelekileyo yeentlungu zangasemva, nangona kunjalo, ngamanye amaxesha ukunyakaza okulula kunokuba neziphumo ezibuhlungu. Ngethamsanqa, ukhetho olulolunye unyango, olufana nokunyamekela kwe-chiropractic, lunokunceda ukunciphisa intlungu emva kokusetyenziswa kohlengahlengiso lomqolo kunye nokunyanzeliswa kwezandla, ekugqibeleni kuphuculwe intlungu. �

I-EXTRA EXTRA | ISIHLOKO ESIBALULEKILEYO: Kunconywe i-El Paso, TX I-Chiropractor

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