Multi-Dimensional Dzimba dzeKetone Bodies

by Dr Alex Jimenez | Anti Aging, Detoxification, Zvokudya, Functional Medicine, utano, Health News El Paso, Holistic Medicine, Ketogenic Diet Yakatsanangurwa, Natural Health, udyo, Kunyanya Kushungurudzika, Remedies, Research Studies, Supplements, Mishonga, Wellness

Mitumbi yeKetone inogadzirwa nechiropa uye inoshandiswa senzvimbo yesimba kana glucose isingawanikwe nyore mumuviri wemunhu. Iyo miviri mikuru ketone miviri iacetoacetate (AcAc) uye 3-beta-hydroxybutyrate (3HB), nepo acetone iri yechitatu uye isinganetsi kuwanda, ketone muviri. MaKetoni anogara aripo muropa uye nhanho dzawo dzinowedzera panguva yekutsanya uye kurovedza muviri kwenguva refuKetogenesis ndiyo inyanzvi yezvinyorwa zvehupenyu izvo zvipenyu zvinogadzira miviri ye ketone kuburikidza nekuparara kwemafuta acids uye ketogenic amino acids.

Zvitunha zveKetone zvinowanzogadzirwa mu mitochondria yeechiropa masero. Ketogenesis inowanikwa apo pane mazinga echechi echeche muropa, zvikurukuru mushure mokunge mamwe masero eklupuhydrate ezvitoro, zvakadai seglycogen, apera. Izvi zvinogonawo kuitika kana pane mashoma mashoma e insulini. Kugadzirwa kwemitumbi yeketone ndiko kwakagadzirirwa kutanga kuita simba rinochengeterwa mumuviri wemunhu semafuta acids. Ketogenesis inowanikwa mumitochondria uko inotungamirirwa zvakasununguka.

ngovepo

Ketone mumuviri metabolism ndiyo node yepamusoro muhutano homeostasis. Muchirongwa ichi, tinokurukura kuti maketoni anoshanda sei maitiro akanaka ekugadzirisa zvirongwa zvemagetsi zvinogadzirisa urongwa uye hupenyu hwehupenyu muhutano hwakasiyana huripo uye hunodzivirira kubva pakuvhiringidza nekukuvadza mune dzimwe nhengo dzehutano. Nenzira dzinoonekwa semagetsi ekugadzirisa zvinongororwa chete mumigodhi yemakrohydrate, kuonekwa kwekupedzisira kunosimbisa kukosha kwemitumbi yeketone seinokosha yemagetsi uye chiratidzo chevanopindirana apo makhahydrates ari akawanda. Kuzadzikisa repertoire yezvinozivikanwa yekurapwa kwezvirwere zvezvirwere zvehutano hwemitsipa, vanotarisira mabasa emaketone emuchirwere ave nekenza, sekuve nekugadzirisa kuchengetedza mabasa mumoyo uye nechiropa, kuvhura nzira dzekurapa muhutano hwakabatana nehutano hwehutano. Kakavhiringidza mu ketone metabolism uye kujekesa kunokurukurwa kuti iyananise chidzidzo chechiGiriki nekucherechedza kwemazuva ano.

ziviso

Mitumbi yeKetone ndeimwe yakakosha svomhu yemafuta maseru ese ehupenyu, eukarya, mabhakitiriya, uye archaea (Aneja et al., 2002; Cahill GF Jr, 2006; Krishnakumar et al., 2008). Ketone muviri metabolism muvanhu yakagadziriswa kuti ipe huropi panguva dzeepisodic nguva dzekushaiwa kwehutano. Mitumbi yeKetone inopindirana nenzira dzakakosha dzemamamia metabolic nzira senge? -Xidation (FAO), iyo tricarboxylic acid kutenderera (TCA), gluconeogenesis, de novo lipogenesis (DNL), uye biosynthesis ye sterols. Mumhuka dzinoyamwisa, miviri ye ketone inogadzirwa zvakanyanya muchiropa kubva kuFAO-yakatorwa acetyl-CoA, uye inoendeswa kune mamwe machira ezvinyama zvekupedzisira oxidation. Iyi physiology inopa imwe mafuta anowedzerwa nenguva pfupi pfupi yekutsanya, iyo inowedzera mafuta acid kuwanikwa uye inoderedza kuwanikwa kwehydrohydrate (Cahill GF Jr, 2006; McGarry naFoster, 1980; Robinson naWillion, 1980). Ketone muviri oxidation inova yakakosha pakupa simba rose mammalian metabolism mukati meexthepatic tishu mune gumi nemaviri epanyama mamiriro, kusanganisira kutsanya, nzara, nguva yekuzvarwa, post-kurovedza muviri, nhumbu, uye kuteedzera kune yakaderera makabhohaidhiretsi dhayeti. Kutenderedza yakazara ketone kuwanda kwemuviri muvanhu vakuru vane hutano kazhinji kunoratidzira macircadian oscillations pakati peanenge 100 250 M, inokwira kusvika ~ 1 mM mushure mekurovedza muviri kwenguva refu kana 24h yekutsanya, uye inogona kuunganidza kusvika pamakumi maviri emamirimita mumatunhu ehutachiona senge chirwere cheshuga ketoacidosis ( Cahill GF Jr, 20; Johnson et al., 2006b; Koeslag et al., 1969; Robinson naWillionon, 1980; Wildenhoff et al., 1980). Chiropa chemunhu chinoburitsa kusvika 1974 g yemitumbi yeketone pazuva (Balasse naFery, 300), iyo inopa pakati pe1989 5% yezvese simba rekushandisa mune dzakadyiwa, dzakatsanya, uye nenzara nyika (Balasse et al., 20; Cox et al., 1978).

Zvidzidzo zvenguva ichangobva zvino zvinosimbisa mabasa anokosha emaketone emaketone mumamenjini masero metabolism, homeostasis, uye kuratidza pasi pemhando dzakasiyana-siyana dzehupenyu uye hutachiona hwehurumende. Kunze kwekushanda semafuta emagetsi emhando dzehutachiona, mwoyo, kana masaga, mitumbi yeketone inobata basa rinokosha sechiratidzo chevatauriri, vatyairi veprotini post-translation modification (PTM), uye ma modulator ekuputika uye kushungurudzika kwehupidhi. Muchidzidzo ichi, tinopa zvose zvechikamu uye zvemazuva ano maonero e pleiotropic emitumbi ye ketone nemasabolism avo.

Kuratidzwa kweKetone Muviri weMetabolism

Chiyero chehepatic ketogenesis chinotungamirirwa neyakagadziriswa nhevedzano yehupenyu uye hwehupenyu hwemakemikari shanduko yemafuta. Vatongi vekutanga vanosanganisira lipolysis ye fatty acids kubva ku triacylglycerols, kutakura kuenda nekuyambuka hepatocyte plasma membrane, kutakura kuenda mitochondria kuburikidza ne carnitine palmitoyltransferase 1 (CPT1), iyo? -Xidation spiral, TCA kutenderera chiitiko uye kwepakati pekufungisisa, redox kugona, uye mahormone regulators yeaya maitiro, kazhinji glucagon uye insulin [yakaongororwa mu (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al., 1983; Kahn et al., 2005; McGarry naFoster. , 1980; Williamson et al., 1969)]. Classical ketogenesis inoonekwa senzira yekutsvaira, umo? -Xidation-inotorwa acetyl-CoA inodarika citrate synthase chiitiko uye / kana oxaloacetate kuwanikwa kwekudzikisira kuita citrate. Vatatu-kabhoni vepakati vanoratidzira anti-ketogenic chiitiko, zvingangodaro nekuda kwekugona kwavo kuwedzera oxaloacetate dziva reacetyl-CoA kushandiswa, asi hepatic acetyl-CoA kusungwa kwega hakuiti ketogenic chiyero (Foster, 1967; Rawat naMenahan, 1975; Williamson et al., 1969). Kugadziriswa kwe ketogenesis nemahormone, zvinyorwa, uye zviitiko zvekushandurudza pamwe chete zvinotsigira pfungwa yekuti mamorekuru maitiro anoteedzera ketogenic chiyero anoramba asina kunyatsonzwisiswa (ona Mutemo weHMGCS2 uye SCOT / OXCT1).

Ketogenesis inowanzoitika mune hepatic mitochondrial matrix pamitengo yakaenzana neiyo yakazara mafuta oxidation. Mushure mekutakurwa kwemaketani eacyl kuyambuka mamitochondrial membranes uye? (Mufananidzo 3A). HMG-CoA lyase (HMGCL) inocheka HMG-CoA kuti isunungure acetyl-CoA uye acetoacetate (AcAc), uye yekupedzisira yakaderedzwa kuita d -? - hydroxybutyrate (d-? OHB) ne phosphatidylcholine-inotenderera mitochondrial d-? OHB dehydrogenase ( BDH2) muNAD + / NADH-yakasanganiswa padyo-equilibrium reaction (Bock naFleischer, 1; LEHNINGER et al., 1). Iyo BDH1975 kuenzana nguva dzose inofarira d- OHB kugadzirwa, asi chiyero cheAcAc / d-? OHB ketone miviri yakanangana zvakananga nemitochondrial NAD + / NADH ratio, uye nekudaro BDH1960 oxidoreductase chiitiko inogadzirisa mitochondrial redox inogona (Krebs et al., 1; Williamson et al., 1). AcAc inogona zvakare kuita zvakasarudzika decarboxylate kune acetone (Pedersen, 1969), sosi yekunhuhwirira kwakanaka muvanhu vanotambura ketoacidosis (kureva., Yakazara serum ketone miviri> ~ 1967 mM; AcAc pKa 1929,? OHB pKa 7). Maitiro anotakurwa nemitumbi yeketone kuyambuka mitochondrial memukati memukati haazivikanwe, asi AcAc / d-? OHB inosunungurwa kubva kumasero kuburikidza ne monocarboxylate vatakuri (mune zvipuka, MCT 3.6 na4.7, inozivikanwawo se solute mutakuri 1A nhengo dzemhuri 2 uye 16) uye kutakurwa mukutenderera kune extrahepatic tishu yemagetsi inoguma (Cotter et al., 1; Halestrap naWilson, 7; Halestrap, 2011; Hugo et al., 2012). Iko kusungirirwa kwekutenderera kwemitumbi yemaketone kwakakwirira kupfuura ayo ari mumatumbu anowedzera (Harrison naLong, 2012) zvichiratidza mitumbi yeketone inoendeswa pasi pechisimba gradient. Kurasikirwa-kwe-basa shanduko muMCT2012 inosanganisirwa neakajairwa mabhaidhi e ketoacidosis, zvichiratidza chinzvimbo chakakosha mukutora kwemuviri kweketone.

Kunze kwekukanganisa kuchinjika kwemitumbi yemaketone mune asina-oxidative maficha (ona Asiri-oxidative metabolic fates yemitumbi yemaketone), hepatocytes inoshaya mukana wekugadzirisa miviri ye ketone yavanogadzira. Mitumbi yeKetone inogadzirwa de novo nechiropa (i) yakaiswa mumitochondria yemamwe mahepisi ane simba kune acetyl-CoA, iyo inowanikwa kune iyo TCA kutenderera kweinoguma oxidation (Fig. 1A), (ii) yakatsauswa kuenda kune lipogenesis kana sterol synthesis nzira ( Fig. 1B), kana (iii) yakaburitswa mumuti. Seimwe simba rinopa simba, mitumbi ye ketone inokosheswa mumoyo, tsandanyama, uye huropi (Balasse naFery, 1989; Bentourkia et al., 2009; Owen et al., 1967; Reichard et al., 1974; Sultan, 1988 ). Extrahepatic mitochondrial BDH1 inokonzeresa maitiro ekutanga eOHB oxidation, ichichinjisa kumashure AcAc (LEHNINGER et al., 1960; Sandermann et al., 1986). Cytoplasmic d-? OHB-dehydrogenase (BDH2) ine 20% chete kuenzanirana kuzivikanwa kweBDH1 ine Km yakakura yemitumbi yemaketone, uye zvakare inoita basa mune ironostostasis (Davuluri et al., 2016; Guo et al., 2006) . Mune extrahepatic mitochondrial matrix, AcAc inoshandiswa kuAcAc-CoA kuburikidza nekuchinjana kweCoA-moiety kubva ku succinyl-CoA mune mhinduro inogadziriswa neakasarudzika mammalian CoA transferase, succinyl-CoA: 3-oxoacid-CoA transferase (SCOT, CoA transferase; encoded by OXCT1), kuburikidza nepedyo yekuenzana reaction. Simba remahara rakaburitswa nehydrolysis yeAcAc-CoA yakakura kudarika iyo ye succinyl-CoA, ichifarira AcAc kuumbwa. Saka ketone muviri oxidative flux inoitika nekuda kwekuita kwakawanda: kuwanda kweAacAc uye nekukurumidza kunwa kweacetyl-CoA kuburikidza necitrate synthase inofarira AcAc-CoA (+ succinate) kuumbwa neSCOT. Zvinonzwisisika, kusiyana neglucose (hexokinase) uye fatty acids (acyl-CoA synthetases), kumisikidzwa kwemitumbi yemaketone (SCOT) mune fomu inogadziriswa haidi kudyara kweATP. Iyo inodzoserwa AcAc-CoA thiolase reaction [yakaomeswa nechero yeana mitochondrial thiolases yakanyorwa ne ACAA2 (encoding enzyme inozivikanwa seT1 kana CT), ACAT1 (encoding T2), HADHA, kana HADHB] inoburitsa mamorekuru maviri eacetyl-CoA, iyo inopinda iyo TCA kutenderera (Hersh naJencks, 1967; Stern et al., 1956; Williamson et al., 1971). Panguva yekototiki nyika (kureva. ; Edmond et al., 500). Chikamu chidiki kwazvo chemitumbi inotorwa nechiropa inogona kuyerwa zviri nyore mumurini, uye mashandisirwo uye kudzoreredza mwero neitsvo zvakaenzana nekutenderera kwevasungwa (Goldstein, 1978; Robinson naWillion, 1989). Munguva yeakanyanya ketotic nyika (> 1987 mM mu plasma), ketonuria inoshanda seyakawandisa-mutori wenhau we ketosis, kunyangwe kazhinji kiriniki yekuyedza yemuviri weti ketone inoona AcAc asi kwete? OHB (Klocker et al., 1987).

Ketogenic Substrates nemigumisiro yavo paHepatocyte Metabolism

Ketogenic substrates dzinosanganisira fatty acids uye amino acids (Fig. 1B). Iyo catabolism ye amino acids, kunyanya leucine, inogadzira pamusoro pe4% yemitumbi miviri yakashambadza mushure mekudzivirira (Thomas et al., 1982). Nokudaro iyo acetyl-CoA substrate dzimba yekuita mitumbi yeketone inowanzobva kumafuta acids, nokuti panguva dzehurumende dzekugadzikana kwemakrohydrate, mvura inopinda inotenderera inonzi TCA cycle zvikurukuru kuburikidza nemaaplerosis, kureva, ATP-dependent carboxylation kune oxaloacetate (OAA), kana kuti marate (MAL), uye kwete oxidative decarboxylation kune acetyl-CoA (Jeoung et al., 2012; Magnusson et al., 1991; Merritt et al., 2011). Muropa, glucose uye pyruvate zvinopa zvisina kufanira ketogenesis, kunyange apo pyruvate decarboxylation kune acetyl-CoA inowedzera (Jeoung et al., 2012).

Acetyl-CoA inowedzera mabasa akawanda ekubatana nehepatic intermediary metabolism kupfuura yechizvarwa cheAATP kuburikidza nekukanganiswa kwechigadziko (uyewo ona Kubatanidzwa kwe ketone muviri metabolism, mushure mokushandura, uye kushandiswa kwefoni). Acetyl-CoA inobatsira kuti i (i) pyruvate carboxylase (PC) ishandise, zvichiita kuti zvirongwa zvekugadzirisa zvirwere zvinokonzera kupindira kwemaetabolites muTCA mhirizhonga (Owen et al., 2002; Scrutton uye Utter, 1967) uye (ii) pyruvate dehydrogenase kinase, iyo phosphorylates uye inhibits pyruvate dehydrogenase (PDH) (Cooper et al., 1975), zvichidaro zvinowedzera kusimbisa kuputika kwepirvo muTCA mumhepo kuburikidza neaplerosis. Uyezve, cytoplasmic acetyl-CoA, ine dziva rinowedzera nezviito zvinoshandura mitochondrial acetyl-CoA kutakura metabolites, inhibits mafuta ehydro oxidation: acetyl-CoA carboxylase (ACC) inobatsira kutendeuka kweAcetyl-CoA kune malonyl-CoA, subpoxy lipogenic uye allosteric inhibitor yemitochondrial CPT1 [yakarongerwa muna (Kahn et al., 2005; McGarry uye Foster, 1980)]. Nokudaro, mitochondrial acetyl-CoA dzimba dzose dzinodzora uye dzinotungamirirwa nemugwagwa unopisa we ketogenesis, unoita kuti zvidimbu zvidimbu zvehuputi hwemagetsi hunogadziriswa.

Kwete-Oxidative Metabolic Fates of Ketone Bodies

Iyo yakanyanya kuguma ye ketoni-yakagadzirwa nemaketoni inonzi SCOT-inotarisira extrahepatic oxidation. Zvisinei, AcAc inogona kutumirwa kubva mitochondria uye inoshandiswa muvanabolic nzira kuburikidza nekushandura kuAcAc-CoA neAtP-dependent reaction inoshandiswa ne cytoplasmic acetoacetyl-CoA synthetase (AACS, Fig. 1B). Nzira iyi inoshanda panguva yekuvandudza kwehuropi uye mukudzikisa mammary gland (Morris, 2005; Robinson naWillionon, 1978; Ohgami et al., 2003). AACS inonyatsorondedzerwa muhutu hwemadii, uye inoshandiswa osteoclasts (Aguilo et al., 2010; Yamasaki et al., 2016). Cytoplasmic AcAc-CoA zvinogona kana nomudzimu cytosolic HMGCS1 vakatarira sterol biosynthesis, kana wakanamatira nokuda kana vaviri cytoplasmic thiolases kuti acetyl-CoA (ACAA1 uye ACAT2), carboxylated kuti malonyl-CoA, uye kubatsirawo kuti kwetunhu mafuta acids (Bergstrom and al., 1984; Edmond, 1974; Endemann et al., 1982; Geelen et al., 1983; Webber uye Edmond, 1977).

Kunyange kukosha kwepanyama kuchiri kuzosimbiswa, ketoni dzinogona kushanda sevanabolic substrates kunyangwe muropa. Mumamiriro ekuedzesera ekugadzirira, AcAc inogona kubatsira kusvika hafu yeiyo ichangobva kugadzirwa lipid, uye inosvika 75% yeyakagadzirwa nyowani cholesterol (Endemann et al., 1982; Geelen et al., 1983; Freed et al., 1988). Nekuti AcAc inotorwa kubva kune isina kukwana hepatic fat oxidation, kugona kweAcA kuendesa kune lipogenesis mu vivo kunoreva hepatic zvisina basa kuchovha, uko maketoni anotorwa nemafuta anogona kushandiswa mukugadzira lipid, pfungwa ine kukosha kwemuviri kunoda kuyedza kusimbisa, asi inogona kushanda adaptive kana maladaptive mabasa (Solinas et al., 2015). AcAc inopa nekukurumidza cholesterogenesis, iine yakaderera AACS Km-AcAc (~ 50 M) inofarira AcAc activation kunyangwe mudunhu rakapihwa (Bergstrom et al., 1984). Basa rine simba re cytoplasmic ketone metabolism yakataurwa mune yekutanga mbeva embryonic neurons uye mu3T3-L1 yakatorwa-adipocyte, seAACS kugogodza kwakakanganisa kusiyaniswa kwemhando imwe neimwe yesero (Hasegawa et al., 2012a; Hasegawa et al., 2012b). Kugogodza kweAACS mumakonzo mu vivo kwakaderera serum cholesterol (Hasegawa et al., 2012c). SREBP-2, a master transcriptional regulator yecholesterol biosynthesis, uye peroxisome proliferator activated receptor (PPAR) -? ndivo maAACS anoshandura anoshanda, uye vanogadzirisa kudhindwa kwaro panguva yekusimudzira neurite uye muchiropa (Aguilo et al., 2010; Hasegawa et al., 2012c). Inotorwa pamwechete, cytoplasmic ketone body metabolism inogona kuve yakakosha mune yakasarudzika mamiriro kana chirwere zvakasikwa nhoroondo, asi haina kukwana kurasa chiropa-inotorwa ketone miviri, sezvo hombe hyperketonemia inoitika mukumisikidza kwekusarudzika kwekukanganisa kweiyo yekutanga oxidative mugumo kuburikidza nekurasikirwa kwehunhu shanduko. ku SCOT (Berry et al., 2001; Cotter et al., 2011).

Mutemo weHMGCS2 uye SCOT / OXCT1

Kusiyana kwemitochondrial kubva kumagetsi ekugadzira cytosolic HMGCS kwakaitika pakutanga kwekushanduka kwemhuka nekuda kwekudiwa kwekutsigira hepatic ketogenesis muzvisikwa zvine uropi hukuru kuhutano hwehuviri (Boukaftane et al., 1994; Cunnane naCrawford, 2003). Zvinokonzerwa nekurasikirwa-kwe-basa HMGCS2 kuchinja kwevanhu kunokonzera kukanganisa kwe hypoketotic hypoglycemia (Pitt et al., 2015; Thompson et al., 1997). Rinoti HMGCS2 kutaura rinongororwa ne hepatocytes uye eponlium colonic, uye maitiro uye maitiro enzymatic anobatanidzwa nenzira dzakasiyana-siyana (Mascaro et al., 1995; McGarry uye Foster, 1980; Robinson naWillion, 1980). Kunyange zvazvo huwandu hwakazara hwehupenyu hunoti hunoita kuti HMGCS2 iwedzere kujekesa, kutaura kwayo uye / kana basa rinotungamirirwa munguva yekusangarika mushure memazuva ekuberekwa, kukwegura, chirwere cheshuga, nzara kana kugoverwa kwekudya kwekotogenic (Balasse uye Fery, 1989; Cahill GF Jr, 2006 ; Girard et al., 1992; Hegardt, 1999; Satapati et al., 2012; Sengupta et al., 2010). Mune fetus, methylation ye5 flanking dunhu reHmgcs2 geni inopindirana nechinyorwa chayo, uye inoshandurwa zvishoma mushure mekuzvarwa (Arias et al., 1995; Ayte et al., 1993; Ehara et al., 2015; Ferre et al. ., 1983). Saizvozvowo, hepatic Bdh1 inoratidzira hutauriri hwekuratidza, iyo inowedzera kubvira pakuberekwa kusvika pakuzorora, uye inokonzerwawo nekutengesa ketogenic mu fibroblast growth factor (FGF) -21-inotenderera (Badman et al., 2007; Zhang et al., 1989 ). Ketogenesis mumararamiro anonyatsoteerera kune zvose insulini uye glucagon, kuregererwa uye kukurudzirwa, maererano (McGarry uye Foster, 1977). Insulin inodzvinyirira adipose tissue lipolysis, nokudaro ichidzivisa ketogenesis ye substrate yayo, nepo glucagon inowedzera ketogenic flux kuburikidza nekukanganisa zvakakwana pachiropa (Hegardt, 1999). Hmgcs2 kudhindwa kunosimudzirwa ne forkhead transcriptional factor FOXA2, iyo inodziviswa ne insulin-phosphatidylinositol-3-kinase / Akt, uye inokonzerwa ne glucagon-cAMP-p300 kuisa chiratidzo (Arias et al., 1995; Hegardt, 1999; Quant et al. , 1990; Thumelin et al., 1993; von Meyenn et al., 2013; Wolfrum et al., 2004; Wolfrum et al., 2003). PPAR? (Rodriguez et al., 1994) pamwechete nechinangwa chayo, FGF21 (Badman et al., 2007) zvakare inokurudzira Hmgcs2 kudhindwa muchiropa panguva yenzara kana manejimendi yekudya ketogenic (Badman et al., 2007; Inagaki et al., 2007 ). Induction yePPAR? zvinogona kuitika kusati kwachinja kubva kune fetal kuenda kuchirwere chemucheche, nepo FGF21 yekumisikidza ichigona kufarirwa munguva yekutanga neonatal kuburikidza neOHB-yakagadziriswa inhibition ye histone deacetylase (HDAC) -3 (Rando et al., 2016). mTORC1 (mammalian chinangwa che rapamycin yakaoma 1) inoenderana nekudzivirira kwePPAR? transcriptional chiitiko zvakare chakakosha mutongi weHmgcs2 gene expression (Sengupta et al., 2010), uye chiropa PER2, tenzi circadian oscillator, zvisina kunangana inodzora kutaura kweHmgcs2 (Chavan et al., 2016). Ongororo dzichangoburwa dzinoratidza kuti extrahepatic bundu-inosimudzira interleukin-6 inokanganisa ketogenesis kuburikidza nePARAR? kudzvinyirira (Flint et al., 2016).

HMGCS2 basa rekunyora maantiki rinotungamirirwa kuburikidza nePTM dzakawanda. HMGCS2 serine phosphorylation yakasimbisa basa rayo mu vitro (Grimsrud et al., 2012). HMGCS2 basa rinenge risina kubvumirana ne succinyl-CoA uye lysine zvakasara zvinopera (Arias et al., 1995; Hegardt, 1999; Lowe uye Tubbs, 1985; Quant et al., 1990; Red et al., 2013; Reed et al., 1975; Thumelin et al., 1993). Succinylation yaHMGCS2, HMGCL, uye BDH1 lysine mabhesi mu mitochondria ye hepatic inopindwa neNAD + inodavirwa neacylase sirtuin 5 (SIRT5) (Rardin et al., 2013). HMGCS2 basa rinosimudzirwawo neSIRT3 lysine deacetylation, uye zvinokwanisika kuti kukwikwidza pakati peacetylation nekushandura kunotungamirira HMGCS2 basa (Rardin et al., 2013; Shimazu et al., 2013). Pasinei nokukwanisa kwePTMs kutonga HMGCS2 Km uye Vmax, kuchinja kwemaPTM aya kusati kwanyatsorongedzwa uye haina kumbosimbiswa sevatengesi vekotogenesis mu vivo.

SCOT inoratidzwa mumasero ose emamamalia anogara mitochondria, kunze kweiyo hepatocytes. Kukosha kwebasa re SCOT uye ketolysis zvakaratidzwa muSCOT-KO mice, iyo yakaratidza kuurayiwa kwunifanana ne hyperketonemic hypoglycemia mukati 48h mushure mokuberekwa (Cotter et al., 2011). Kurasikirwa kwemavara kweCOT in neurons kana skeletal myocytes inokonzera kusagadzikana kwemagetsi panguva yekushaya nzara asi kwete kuuraya (Cotter et al., 2013b). Muvanhu, kushaikwa kwechikwata kunounza pakutanga kweupenyu ne ketoacidosis yakakomba, zvichikonzera kutadza, kurutsa, uye coma (Berry et al., 2001; Fukao et al., 2000; Kassovska-Bratinova et al., 1996; Niezen-Koning et al. , 1997; Saudubray et al., 1987; Snyderman et al., 1998; Tildon uye Cornblath, 1972). Zvichida zvishoma zvinonyatsozivikanwa pamasero emagetsi pamusoro peSOT gene uye mapuroteni expression regulators. Oxct1 mRNA kutaura uye SCOT protein uye basa zvakaderera mu ketotic states, zvichida kuburikidza nePARAR-dependent mechanisms (Fenselau naWallis, 1974; Fenselau naWallis, 1976; Grinblat et al., 1986; Okuda et al., 1991; Turko et al ., 2001; Wentz et al., 2010). Mu chirwere cheshuga ketoacidosis, kusagadzikana pakati pehepatic ketogenesis uye extrahepatic oxidation inowedzera kukura kwechiitiko cheCOT. Kunyanya kufungidzira kwe insulini-yakasununguka glucose transporter (GLUT1 / SLC2A1) mu cardiomyocytes inhibitswo Oxct1 gene kutaura uye inoderedza maketone ekugadziriswa kwekupedzisira mune imwe nyika isiri ketotic (Yan et al., 2009). Muropa, Oxct1 mRNA yakawanda inodzvinyirirwa ne microRNA-122 uye histone methylation H3K27me3 iyo inowanikwa panguva yekushanduka kubva pakuberekwa kusvika kune nguva yekuberekwa (Thorrez et al., 2011). Zvisinei, kudzvinyirirwa kwehepatic Oxct1 kutaura mumashure ekuberekwa kunonyanya kukonzerwa nekubudiswa kweOxct1-kuratidza hematopoietic progenitors kubva pachiropa, pane kurasikirwa kwekare kwaivepo yeOxct1 kutaura kusinganzwisisiki hepatocytes. Kutaura zvazviri, kutaura kweOxct1 mRNA uye SCOT protein inoparadzaniswa nehepatocytes yakadzika zvikuru (Orii et al., 2008).

SCOT inogadziriswawo nemaPTM. Iyo enzyme ine hyper-acetylated muhuropi hweSIRT3 KO mbeva, iyo zvakare inoratidza kuderedzwa kweAcAc inoenderana acetyl-CoA kugadzirwa (Dittenhafer-Reed et al., 2015). Isiri-enzymatic nitration ye tyrosine masara eSCOT zvakare anokanganisa mashandiro ayo, ayo akataurwa mumoyo yemarudzi akasiyana siyana eshuga mhando (Marcondes et al., 2001; Turko et al., 2001; Wang et al., 2010a). Mukupesana, tryptophan residue nitration inowedzera maitiro eSCOT (Br g re et al., 2010; Rebrin et al., 2007). MaMolekorori masarasara-akasarudzika nitration kana de-nitration yakagadzirirwa kuteedzera SCOT chiitiko chingave chiripo uye chinoda kujekeswa.

Zvinokakavadzana mu Extrahepatic Ketogenesis

Mune mammals iyo yekutanga ketogenic nhengo chiropa, uye chete hepatocytes uye gut epithelial maseru anonyanya kuratidza iyo mitochondrial isoform yeHMGCS2 (Cotter et al., 2013a; Cotter et al., 2014; McGarry naFoster, 1980; Robinson naWillionon, 1980) . Anaerobic bacterial Fermentation yezvakaoma polysaccharides inoburitsa butyrate, iyo inosvitswa nemakolonocytes mumamamaria eiyo terminal oxidation kana ketogenesis (Cherbuy et al., 1995), iyo inogona kutora chinzvimbo mukuparadzanisa kwekolonocyte (Wang et al., 2016). Kunze kwematumbo epithelial maseru uye hepatocyte, HMGCS2 ingangove isipo mune mamwe ese mammalian maseru, asi tarisiro ye extrahepatic ketogenesis yakakwidziridzwa mumatumbu maseru, astrocytes epakati sisitimu yetsinga, itsvo, pancreatic? masero, retinal pigment epithelium (RPE), uye kunyangwe mumhasuru yemhasuru (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 yakaonekwa mumatukisi anoshaya net ketogenic kugona (Cook et al., 2016; Wentz et al., 2010), uye HMGCS2 inoratidza zvingangoita ketogenesis-yakazvimirira moonlighting zviitiko, kusanganisira mukati memusero weneru (Chen et al. , 2016; Kostiuk et al., 2010; Meertens et al., 1998).

Chero chipi nechipi extrahepatic tishu inosanganisa ketone miviri zvakare ine mukana wekuunganidza ketone miviri kuburikidza neHMGCS2 yakazvimirira nzira (Fig. 2A). Nekudaro, hapana imwe nyama yeaphephepatic umo kugadzikana kwenyika ketone yemuviri inodarika iyo mukutenderera (Cotter et al., 2011; Cotter et al., 2013b; Harrison uye Long, 1940), ichisimbisa kuti mitumbi yeketone inoendeswa pasi concentration gradient kuburikidza neMCT1 / 2-inoenderana nzira. Imwe nzira yezviri pachena extrahepatic ketogenesis inogona kuratidza kukanganisika kweiyo ketone oxidation. Dzimwe tsananguro dzinogona kuitika dzinowira mukati mekamuri yekuumbwa kwemaketone. Kutanga, de novo ketogenesis inogona kuitika kuburikidza nekudzosera enzymatic chiitiko che thiolase uye SCOT (Weidemann na Krebs, 1969). Kana iko kusunganidzwa kweacetyl-CoA kwakanyanya kukwirisa, maitiro anowanzoitirwa AcAc oxidation anoshanda munzira yekumashure (GOLDMAN, 1954). Yechipiri mashandiro inoitika kana? -Xidation-inotorwa mapakati anoungana nekuda kweiyo TCA kutenderera bhodhoro, AcAc-CoA inoshandurwa kuita l-? OHB-CoA kuburikidza nemhinduro inogadziriswa ne mitochondrial 3-hydroxyacyl-CoA dehydrogenase, uyezve ne3-hydroxybutyryl CoA deacylase kune l- OHB, iyo isinganzwisisike nehukuru hwemasitrometry kana resonance spectroscopy kubva kune epanyama enantiomer d-? OHB (Reed uye Ozand, 1980). l- OHB inogona kuve chromatographically kana enzymatic kusiyaniswa kubva kune d- OHB, uye iripo mune extrahepatic tishu, asi kwete muchiropa kana muropa (Hsu et al., 2011). Hepatic ketogenesis inogadzira chete d-? OHB, iyo yega enantiomer iri BDH substrate (Ito et al., 1984; Lincoln et al., 1987; Reed naOzand, 1980; Scofield et al., 1982; Scofield et al., 1982). Yechitatu HMGCS2-yakazvimirira mashandiro inogadzira d- OHB kuburikidza neamino acid catabolism, kunyanya iyo leucine uye lysine. Chechina mashandiro anongoratidzika nekuti imhaka yechiratidzo chekunyora uye nekudaro inonzi pseudoketogenesis. Ichi chiitiko chinokonzerwa nekudzokororwa kweSCOT uye thiolase reaction, uye zvinogona kukonzera overestimation ye ketone muviri kutendeuka nekuda kwesotopic kudzora ketone body tracer mune extrahepatic tishu (Des Rosiers et al., 1990; Fink et al., 1988) . Kunyange zvakadaro, pseudoketogenesis inogona kunge isingakoshese mune dzakawanda mamiriro (Bailey et al., 1990; Keller et al., 1978). A schematic (Fig. 2A) inoratidza nzira inobatsira yekushandisa uchitarisa zvakakwirisa zvinyama zvakadzikama mamiriro emaketoni.

Itsvo ichangobva kugamuchirwa senhengo inogona kuita ketogenic. Mune ruzhinji rwematunhu, itsvo mutengi mutengi weakatorwa-chiropa ketone miviri, achiburitsa kana kudzoreredza miviri ye ketone kubva muropa, uye itsvo kazhinji haisi netone ketone muviri jenareta kana concentrator (Robinson naWillion, 1980). Vanyori vechinyakare kudzidza vakapedzisa kuti mashoma renal ketogenesis akaenzana mune yekuyedza yekuyedza system yakanga isiri physiologically yakakosha (Weidemann naKrebs, 1969). Munguva pfupi yapfuura, renal ketogenesis yakaiswa mune chirwere cheshuga uye kuzvidzora kushomeka mbeva mhando, asi zvinowanzoitika kuti kuwanda-nhengo shanduko mune metabolic homeostasis inoshandura inosanganisa ketone metabolism kuburikidza nekuisa pane akawanda mitezo (Takagi et al., 2016a; Takagi et al., 2016b; Zhang et al., 2011). Rimwe bhuku razvino rakaratidza renal ketogenesis senzira yekudzivirira kurwisa ischemia-reperfusion kukuvara muitsvo (Tran et al., 2016). Mhedzisiro yakadzikama mamiriro emamiriro eOHB kubva pane zvigadzirwa zvemakonzo renal tishu zvakataurwa pa ~ 4 12 mM. Kuti tiongorore kana izvi zvaikwanisika, isu takaverenga? OHB yakatarwa muzvibodzwa zvetsvo kubva kumafuru uye 24h makonzo akatsanya. Serum? OHB kukosheswa kwakawedzera kubva pa ~ 100 M kusvika pa2 mM ine 24h yekutsanya (Fig. 2B), nepo renal rakadzikama nyika? OHB kuwanda kunosvika 100 M mudunhu rakapihwa, uye chete 1 mM mune iyo 24h yakatsanya nyika (Fig. 2C E), kucherechedzwa kunoenderana nekufungidzirwa kwakaitwa pamusoro pemakore makumi mana nemashanu apfuura (Hems naBrosnan, 45). Izvo zvinoramba zvichigoneka kuti mune ketotic nyika, chiropa-inotorwa ketone miviri inogona kuve yekuzvidzivirira zvakare, asi humbowo hwe renal ketogenesis inoda kumwe kusimbisa. Uchapupu hunogombedzera hunotsigira hwechokwadi extrahepatic ketogenesis yakaunzwa muRPE (Adijanto et al., 1970). Iyi inonakidza metabolic shanduko yakapihwa mukana wekubvumidza RPE-yakatorwa ketoni kuyerera kune photoreceptor kana M ller glia maseru, ayo anogona kubatsira mukumutsiridzwa kweiyo photoreceptor yekunze chikamu.

OHB seMurevereri Anoratidza

Kunyangwe ivo vakapfuma zvine simba, ketone miviri inopa inokanganisa non-canonical yekuratidzira mabasa mumaseru homeostasis (Fig. 3) (Newman naVerdin, 2014; Rojas-Morales et al., 2016). Semuenzaniso, OHB inodzivisa Kirasi I HDACs, iyo inowedzera histone acetylation uye nokudaro inokonzeresa kutaura kwemajini anoderedza kushushikana kweiyo oxidative (Shimazu et al., 2013). OHB pachayo inonzi histone covalent modifier pane lysine masara mune zviropa zvekutsanya kana streptozotocin inokonzera chirwere cheshuga (Xie et al., 2016) (onawo pazasi, Kubatanidzwa kwe ketone body metabolism, post-translational modification, uye cell physiology, uye Ketone miviri, oxidative kusagadzikana, uye neuroprotection).

OHB zvakare inogadzira kuburikidza neG-protein yakasanganiswa receptors. Kubudikidza nekusajeka kwema molecular maitikiro, inodzvinyirira inonzwira tsitsi hunyanzvi chiitiko uye inoderedza yakazara simba rekushandisa uye nemoyo kurovera nekudzivisa pfupi keteni mafuta asidi kuratidza kuburikidza neG protein yakasangana receptor 41 (GPR41) (Kimura et al., 2011). Imwe yeakanyanya kudzidza kusaina mhedzisiro yeOHB inopfuurira kuburikidza neGPR109A (inozivikanwawo seHCAR2), nhengo yehydrocarboxylic acid GPCR sub-mhuri inoratidzwa mune adipose tishu (chena uye shava) (Tunaru et al., 2003), uye mu immune maseru (Ahmed et al., 2009). OHB ndiyo yega inozivikanwa endo native ligand yeGPR109A receptor (EC50 ~ 770 M) yakaitwa ne d- OHB, l- OHB, uye butyrate, asi kwete AcAc (Taggart et al., 2005). Iyo yepamusoro yevasungwa chikumbaridzo cheGPR109A activation inoitwa kuburikidza nekuteerera kune ketogenic kudya, nzara, kana panguva yeketoacidosis, zvichitungamira mukudzivirirwa kweadipose tishu lipolysis. Iyo anti-lipolytic mhedzisiro yeGPR109A inoenderera kuburikidza nekudzivirira kweadenylyl cyclase uye yakadzikira cAMP, ichivhiringidza mahormone sensitive triglyceride lipase (Ahmed et al., 2009; Tunaru et al., 2003). Izvi zvinogadzira yakashata mhinduro loop umo ketosis inoisa modulatory brake pane ketogenesis nekudzora kuburitswa kweasina-esterified fatty acids kubva kune adipocytes (Ahmed et al., 2009; Taggart et al., 2005), mhedzisiro inogona kuenzaniswa ne iyo yekunzwira tsitsi iyo inomutsa lipolysis. Niacin (vhitamini B3, nicotinic acid) ine simba (EC50 ~ 0.1 M) ligand yeGRP109A, inonyatsoshandiswa kwemakumi emakore kune dyslipidemias (Benyo et al., 2005; Benyo et al., 2006; Fabbrini et al., 2010a; Lukasova et al., 2011; Tunaru et al., 2003). Ipo niacin inowedzera inodzosera cholesterol kutakura mune macrophages uye ichideredza atherosclerotic maronda (Lukasova et al., 2011), mhedzisiro yeOHB pazvironda zveatherosclerotic hazvizivikanwe. Kunyangwe GPR109A receptor iine mabasa ekudzivirira, uye kubatana kunonakidza kuripo pakati pekudya ketogenic mukurohwa uye neurodegenerative zvirwere (Fu et al., 2015; Rahman et al., 2014), chinodzivirira che OHB kuburikidza neGPR109A hachina kuratidzwa mu vivo .

Chekupedzisira, OHB inogona kukanganisa kudya uye kuguta. Meta-ongororo yezvidzidzo zvakayera mhedzisiro yeketogenic uye yakaderera kwazvo simba rekudya yakagumisa kuti vatori vechikamu vanodya izvi zvikafu vanoratidza kuguta kwakanyanya, zvichienzaniswa nedhayeti yekudzora (Gibson et al., 2015). Nekudaro, tsananguro inonzwisisika yemhedzisiro iyi ndeyekuwedzera metabolic kana mahormone ezvinhu anogona kuenzanisa chishuwo. Semuenzaniso, mbeva dzakachengetedzwa pane imwe pentent ketogenic chikafu chakaratidza kuwedzerwa kwesimba kwemagetsi kana ichienzaniswa necow kudzora-dzakapa mbeva, kunyangwe zvakafanana macaloric kudya, uye kutenderera leptin kana mageneti epeptide anoronga maitiro ekudyisa haana kuchinjwa (Kennedy et al., 2007). Pakati penzira dzakarongwa dzinoratidza kudzvinyirira kudya neOHB inosanganisira zvese zvinoratidza uye oxidation (Laeger et al., 2010). Hepatocyte chaiyo kubviswa kweiyo circadian riyamu geni (Per2) uye chromatin immunoprecipitation zvidzidzo zvakaburitsa pachena kuti PER2 inogonesa iyo Cpt1a geni, uye zvisina kunangana inodzora Hmgcs2, zvichitungamira kune yakakanganisika ketosis muPer2 kugogodza mbeva (Chavan et al., 2016). Idzi mbeva dzakaratidza kushomeka kwekufungidzira kwechikafu, icho chakadzoserwa chikamu nehurongwa? OHB manejimendi. Zvidzidzo zvenguva yemberi zvichazodiwa kusimbisa iyo yepakati tsinga senzira yakananga? OHB tarisiro, uye kana ketone oxidation inodiwa kune inoonekwa mhedzisiro, kana kana imwe chiratidzo chiratidzo inobatanidzwa Vamwe vaongorori vakadenha mukana weiyo yemunharaunda astrocyte-yakatorwa ketogenesis mukati meiyo ventromedial hypothalamus semutongi wekudya chikafu, asi izvi zvekutanga kucherechedzwa zvakare zvinobatsira kubva kumageneti uye flux-based ongororo (Le Foll et al., 2014). Hukama huripo ketosis nekushaiwa kwehutano kunoramba kuri kwekufarira nekuti nzara uye kuguta zvinhu zvakakosha mukukundikana kwekudzikira kuonda.

Kusanganiswa kweKetone Mutumbi weMetabolism, Post-Translational Modification, uye Cell Physiology

Zvitunha zveKetone zvinobatsira kumadzimai emagetsi eAacetyl-CoA, iyo inokosha inonyanya kuratidza basa rinokosha mumagetsi emagetsi (Pietrocola et al., 2015). Rimwe basa reAcetyl-CoA nderokushanda se substrate ye acetylation, iyo enzymatically-catalyzed histone covalent modification (Choudhary et al., 2014; Dutta et al., 2016; Fan et al., 2015; Menzies et al., 2016 ). Nhamba yakawanda ye-dynamically acetylated mitochondrial proteins, iyo yakawanda inogona kuitika kuburikidza nemichina isiri-enzymatic, yakabudawo kubva kumashonga ekudzidzira mapurogiramu (Dittenhafer-Reed et al., 2015; Hebert et al., 2013; Rardin et al., 2013 ; Shimazu et al., 2010). Lysine deacetylases vanoshandisa zinc cofactor (eg, nucleocytosolic HDACs) kana NAD + se-co-substrate (sirtuins, SIRTs) (Choudhary et al., 2014; Menzies et al., 2016). I-acetylproteome inoshandisa senzwi uye inokonzera yezana rose acetyl-CoA dziva, sepanyama uye maitiro ezvimwewo zvinokonzera kusina-enzymatic kuparadzaniswa kwepasi rose kweacetylation (Weinert et al., 2014). Sezvo intracellular metabolites inoshanda semodulator ye-lysine yakasara acetylation, zvinokosha kufunga nezvemaitiro emitumbi yeketone, iyo yakawanda ine simba zvikuru.

OHB ndeye epigenetic modifier kuburikidza nenzira mbiri. Kuwedzera? OHB mazinga anokonzerwa nekutsanya, caloric kurambidzwa, kutungamira kwakananga kana kwenguva refu kurovedza muviri kunokanganisa HDAC inhibition kana histone acetyltransferase activation (Marosi et al., 2016; Sleiman et al., 2016) kana kune oxidative kusagadzikana (Shimazu et al., 2013) . OHB inhibition yeHDAC3 inogona kudzora achangozvarwa metabolic physiology (Rando et al., 2016). Kuzvimiririra,? OHB pachayo inoshandura zvakananga histone lysine masara (Xie et al., 2016). Kutsanya kwenguva refu, kana steptozotocin-inosimudzira chirwere cheshuga ketoacidosis yakawedzera histone? -Hydroxybutyrylation. Kunyangwe iyo nhamba yeLysine? -Hydroxybutyrylation uye acetylation saiti yaive yakafanana, stoichiometrically yakakura histone? -Hydroxybutyrylation pane acetylation yakaonekwa. Mageneti akaparadzaniswa akakanganiswa ne histone lysine? -Hydroxybutyrylation, maringe neacetylation kana methylation, zvichiratidza zvakasiyana maseru mashandiro. Zvingave? -Hydroxybutyrylation inongoitika kana enzymatic haina kuzivikanwa, asi inowedzera huwandu hwenhanho kuburikidza nemitumbi yemaketone zvine simba kukurudzira kudhindwa.

Zvakakosha masero ekuronga zvakare zviitiko panguva yekarori kudzivirirwa uye kushomeka kwehutano kunogona kupindirana muSIRT3- uye SIRT5-inoenderana nemitochondrial deacetylation uye desuccinylation, zvichiteerana, kudzora ketogenic uye ketolytic mapuroteni pamashure-ekushandura chikamu muchiropa uye extrahepatic tishu (Dittenhafer-Reed et al., 2015; Hebert et al., 2013; Rardin et al., 2013; Shimazu et al., 2010). Kunyangwe stoichiometric kuenzanisa kwenzvimbo dzinogarwa hazvireve kuti zvinobatanidza zvakananga nekuchinja mune metabolic flux, mitochondrial acetylation ine simba uye inogona kutungamirwa neacetyl-CoA yevasungwa kana mitochondrial pH, pane enzymatic acetyltransferases (Wagner naPayne, 2013). Iyo SIRT3 uye SIRT5 inoteedzera zviitiko zve ketone muviri inogadzirisa ma enzymes inokonzeresa mubvunzo webasa rekudzokorora emaketoni mukuveza iyo acetylproteome, succinylproteome, uye zvimwe zvinesimba maseru tarisiro. Chokwadi, sekusiyana kwe ketogenesis inoratidza kuwanda kweNAD +, kugadzirwa kweketone uye kuwanda kunogona kudzora sirtuin chiitiko, zvichidaro kukanganisa huwandu hwesetetyl-CoA / succinyl-CoA madziva, iyo acylproteome, uye nekudaro mitochondrial uye cell physiology. ? -hydroxybutyrylation ye enzyme lysine masara anokwanisa kuwedzera imwe dura kune repamagetsi reprogramming. Mune extrahepatic tishu, ketone muviri oxidation inogona kukurudzira fanano shanduko mune cell homeostasis. Ipo kupatsanurwa kwemadziva eacetyl-CoA akanyanya kugadziriswa uye achigadzirisa huwandu hwakawanda hwekushanduka kwemaseru, kugona kwemitumbi yeketone kuumba zvakananga mitochondrial uye cytoplasmic acetyl-CoA zvinoda kujekeswa (Chen et al., 2012; Corbet et al., 2016; Pougovkina et al., 2014; Schwer et al., 2009; Wellen naT Thompson, 2012). Nekuti acetyl-CoA kuwanda kwakanyatsorongedzwa, uye acetyl-CoA inhengo isina kukwana, zvakakosha kuti tifunge nzira dzekutyaira dzinobata acetyl-CoA homeostasis, kusanganisira mitengo yekugadzira uye yekupedzisira oxidation muTCA kutenderera, kushandurwa kuita ketone miviri, mitochondrial efflux kuburikidza necarnitine acetyltransferase (CrAT), kana acetyl-CoA kutumira kune cytosol mushure mekushandurwa kuita citrate uye kuburitswa neATP citrate lyase (ACLY). Iwo akakosha mabasa eaya ekupedzisira mashandiro musero acetylproteome uye homeostasis zvinoda kuenderana kunzwisisa kwemabasa e ketogenesis uye 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 na Thompson, 2012). Shanduko matekinoroji mumetabolomics uye acylproteomics mukumisikidzwa kwemajini anoshandiswa anozodikanwa kutsanangura zvinangwa uye mhedzisiro.

Zvirwere zveAn anti- uye Pro-Inflammatory ku Ketone Bodies

Ketosis uye ketone miviri inoteedzera kuzvimba uye immune cell mashandiro, asi akasiyana uye kunyange akasiyana maitiro akagadziriswa. Kurasikirwa kwenguva refu kwehutano kunoderedza kuzvimba (Youm et al., 2015), asi isingaperi ketosis yerudzi rwe1 chirwere cheshuga inzvimbo yekuzvimba (Jain et al., 2002; Kanikarla-Marie naJain, 2015; Kurepa et al., 2012 ). Mechanism-yakavakirwa yekuratidzira mabasa eOHB mukuzvimba inobuda nekuti akawanda immune system maseru, anosanganisira macrophage kana monocyte, anonyatsoratidza GPR109A. Ipo? OHB ine mhinduro inopesana nekuzvimba (Fu et al., 2014; Gambhir et al., 2012; Rahman et al., 2014; Youm et al., 2015), kukwirira kwakanyanya kwemitumbi yeketone, kunyanya AcAc, inogona kukonzera pro-kupisa mhinduro (Jain et al., 2002; Kanikarla-Marie naJain, 2015; Kurepa et al., 2012).

Anti-anogumbura mabasa eGPR109A ligands mune atherosclerosis, kufutisa, hutachiona hwechirwere, chirwere chetsinga, uye kenza yakaongororwa (Graff et al., 2016). GPR109A kutaura kunowedzerwa muRPE maseru ezve diabetic modhi, vanhu vane chirwere cheshuga (Gambhir et al., 2012), uye mu microglia panguva yeurodegeneration (Fu et al., 2014). Anti-anogumbura mhedzisiro? OHB inowedzerwa neGPR109A overexpression mumaRPE maseru, uye yakabviswa nehutachiona hwekudzivirira kana kugogodza kwemajini kweGPR109A (Gambhir et al., 2012). OHB uye yakawandisa nicotinic acid (Taggart et al., 2005), ese anopa kurwisa-kuzvimba mhedzisiro muTNF? kana LPS-inokonzeresa kuzvimba nekudzora iwo mazinga epro-anogumbura mapuroteni (iNOS, COX-2), kana yakavigwa cytokines (TNF? IL-1?, IL-6, CCL2 / MCP-1), muchidimbu kuburikidza nekudzivirira NF -? B kufambisa (Fu et al., 2014; Gambhir et al., 2012). OHB inoderedza kushushikana kweER uye iyo NLRP3 inflammasome, ichigadzirisa iyo antioxidative kusagadzikana kupindura (Bae et al., 2016; Youm et al., 2015). Nekudaro, mune neurodegenerative kuzvimba, GPR109A-inoenderana? OHB-inodzivirirwa dziviriro haibatanidzi vanoputira vamiririri senge MAPK nzira yekusaina (semuenzaniso, ERK, JNK, p38) (Fu et al., 2014), asi inogona kuda COX-1-inoenderana nePGD2. kugadzirwa (Rahman et al., 2014). Zvinonakidza kuti macrophage GPR109A inodikanwa kuti ishandise maitiro europrotective mune ischemic sitiroko modhi (Rahman et al., 2014), asi kugona kweOHB kudzvinyirira iyo NLRP3 inflammasome mumapfupa emapfupa akatorwa macrophages GPR109A yakazvimiririra (Youm et al. ., 2015). Kunyange hazvo zvidzidzo zvakawanda zvichibatanidza OHB kune anti-anogumbura mhedzisiro, OHB inogona kunge iri-yekuzvimba uye ichiwedzera mamaki eepid peroxidation mumhuru hepatocytes (Shi et al., 2014). Anti- maringe nepro-kuzvimba mhedzisiro yeOHB inogona kudarikidza nemhando yesero, OHB kusangana, nguva yekuratidzira, uye kuvapo kana kusavapo kweva-modulators.

Kusiyana neOHB, AcAc inogona kumisikidza chiratidzo che-pro-inflammatory. Yakakwidziridzwa AcAc, kunyanya iine yakakwira glucose yevasungwa, inowedzera endothelial cell kukuvara kuburikidza neNADPH oxidase / oxidative kushungurudzika kunoenderana maitiro (Kanikarla-Marie naJain, 2015). Yakakwira AcAc kuwanda mune umbilical tambo yeanamai vane chirwere cheshuga yakanga yakabatana neakakwira mapuroteni oxidation mwero uye MCP-1 kusangana (Kurepa et al., 2012). Yakakwira AcAc mune vane chirwere cheshuga varwere yakanga yakabatana neTNF? kutaura (Jain et al., 2002), uye AcAc, asi kwete? OHB, yakakonzera TNF?, MCP-1 kutaura, kuunganidzwa kweROS, uye kudzikira kwenzvimbo yeCAMP muU937 masero emunhu monocyte (Jain et al., 2002; Kurepa et al. ., 2012).

Ketone inoenderana nemasaini chiratidzo chezviitiko zvinowanzo kukonzerwa chete neakanyanya ketone muviri kuwanda (> 5 mM), uye mune kesi yezvakawanda zvidzidzo zvinobatanidza ketoni kune pro- kana anti-kupisa mhedzisiro, kuburikidza nenzira dzisina kujeka. Uye zvakare, nekuda kwemakakatanwa emhedzisiro? OHB maringe neAc pakuzvimba, uye kugona kweAcAc /? OHB chiyero chekukanganisa mitochondrial redox kugona, kwakanyanya kuyedza kuongorora mabasa emaketone miviri pane maseru phenotypes enzanisa mhedzisiro yeAcAc uye? OHB mumatanho akasiyana, uye pamatanho akasiyana ekuwedzera [semuenzaniso, (Saito et al., 2016)]. Chekupedzisira, AcAc inogona kutengwa zvekutengesa chete se lithiamu munyu kana seethyl ester iyo inoda base hydrolysis isati yashandiswa. Lithium cation yakazvimiririra inokonzeresa kutapurirana kwemasaini (Manji et al., 1995), uye AcAc anion iri labile. Chekupedzisira, zvidzidzo zvinoshandisa racemic d / l-? OHB inogona kunyadziswa, sezvo chete iyo d-? OHB stereoisomer inogona kusanganiswa kune AcAc, asi d-? OHB uye l- OHB inogona chiratidzo chimwe nechimwe kuburikidza neGPR109A, inhibvisa iyo NLRP3 inflammasome, uye unoshanda se lipogenic substrates.

Ketone Bodies, Oxidative Stress, uye Neuroprotection

Kushushikana nekushushikana kunowanzo tsanangurwa senyika iyo iyo ROS inoratidzwa zvakawandisa, nekuda kwekunyanyisa kugadzirwa uye / kana kukanganisika kubvisa. Antioxidant uye oxidative kushushikana kudzikamisa mabasa emaketone miviri ave achinyatsotsanangurwa zvese mu vitro uye mu vivo, kunyanya mune mamiriro europrotection. Sezvo maNeuron mazhinji asinganyatso kuburitsa yakakwira-simba phosphates kubva kumafuta acids asi ita oxidize ketone miviri kana makabhohaidhiretsi ari kushomeka, neuroprotective mhedzisiro yemitumbi yemaketone inonyanya kukosha (Cahill GF Jr, 2006; Edmond et al., 1987; Yang et al., 1987). Mune oxidative kusagadzikana mhando, BDH1 induction uye SCOT kudzvinyirira zvinoratidza kuti ketone muviri metabolism inogona kugadziriswazve kuchengetedza akasiyana maseru chiratidzo, redox kugona, kana metabolic zvinodiwa (Nagao et al., 2016; Tieu et al., 2003).

Mitumbi yeKetone inoderedza mamakisi ekukuvara kwemaseru, kukuvara, kufa uye kudzika apoptosis mueuron uye cardiomyocyte (Haces et al., 2008; Maalouf et al., 2007; Nagao et al., 2016; Tieu et al., 2003). Maitiro akakweretwa akasiyana uye kwete nguva dzose zvine mutsindo zvine chekuita nekufungisisa. Low millimolar kuwanda kwe (d kana l) -? OHB inotsvaira ROS (hydroxyl anion), nepo AcAc ichikwenya mhando dzakawanda dzeROS, asi chete pazvikamu zvinopfuura huwandu hwepanyama (IC50 20-67 mM) (Haces et al., 2008) . Ukuwo, simba rinobatsira pamusoro peelectron yekufambisa cheni redox kugona ndiyo nzira inowanzo sunganidzwa ne d-? OHB. Kunyange miviri yese ketone miviri (d / l-? OHB uye AcAc) yakaderedza neuronal cell kufa uye kuunganidzwa kweROS kunokonzerwa nemakemikari inhibition yeglycolysis, chete d- OHB uye AcAc zvakadzivirira neuronal ATP kuderera. Ukuwo, mune hypoglycemic mu vivo modhi, (d kana l) - OHB, asi kwete AcAc inodzivirira hippocampal lipid peroxidation (Haces et al., 2008; Maalouf et al., 2007; Marosi et al., 2016; Murphy, 2009 ; Tieu et al., 2003). Mune vivo zvidzidzo zvemakonzo akadyisa chikafu che ketogenic (87% kcal mafuta uye 13% protein) yakaratidza neuroanatomical kusiyanisa kweiyo antioxidant kugona (Ziegler et al., 2003), uko shanduko dzakadzama kwazvo dzakaonekwa muhippocampus, iine kuwedzera glutathione peroxidase uye yakazara antioxidant kugona.

Ketogenic kudya, ketone esters (onawo Kurapa kwekushandisa kwe ketogenic kudya uye exogenous ketone miviri), kana? OHB manejimendi inoshandisa neuroprotection mumhando yeschemic sitiroko (Rahman et al., 2014); Chirwere chePasinson (Tieu et al., 2003); central nervous system oksijeni huturu hwekubata (D'Agostino et al., 2013); pfari pfari (Yum et al., 2015); mitochondrial encephalomyopathy, lactic acidosis uye stroke-like (MELAS) episodes syndrome (Frey et al., 2016) uye chirwere cheAlzheimer (Cunnane naCrawford, 2003; Yin et al., 2016). Zvichakadaro, gwaro richangoburwa rakaratidza humbowo hwehutachiona hwehutachiona hwehutachiona hwehutachiona hweketogenic mune mutserendende mbeva modhi yekushomeka kwemitochondrial DNA kugadzirisa, kunyangwe ichiwedzera masitochondrial biogenesis nemasainiantioidantiantant (Lauritzen et al., 2016). Mimwe mishumo inopesana inoratidza kuti kuratidzirwa kune yakanyanya ketone kuwanda kwemuviri kunokonzeresa kushushikana kweiyo oxidative. Yakakwirira? OHB kana AcAc doses inokonzera nitric oxide secretion, lipid peroxidation, yakaderedzwa kutaura kweSOD, glutathione peroxidase uye catalase mumhuru hepatocytes, nepo mumakonzo hepatocytes iyo MAPK nzira yekumisikidzwa yakanzi kune AcAc asi kwete? OHB (Abdelmegeed et al., 2004 ; Shi et al., 2014; Shi et al., 2016).

Inotorwa pamwechete, yakawanda mishumo inobatanidza? OHB kudzvinyirira kweiyo oxidative kusagadzikana, sezvo manejimendi yayo ichitadzisa kugadzirwa kweROS / superoxide, inodzivirira lipid peroxidation uye protein oxidation, inowedzera antioxidant mapuroteni mazinga, uye inovandudza kufema kwemitochondrial uye kugadzirwa kweATP (Abdelmegeed et al., 2004; Haces et al., 2008; Jain et al., 1998; Jain et al., 2002; Kanikarla-Marie naJain, 2015; Maalouf et al., 2007; Maalouf naRho, 2008; Marosi et al., 2016; Tieu. et al., 2003; Yin et al., 2016; Ziegler et al., 2003). Nepo AcAc yanga ichinyatso kuenderana kupfuura OHB pamwe nekuiswa kweiyo oxidative kusagadzikana, izvi mhedzisiro hazviwanzo kupatsanurwa nyore nyore kubva kune vangango tarira kuzvidzivirira mhinduro (Jain et al., 2002; Kanikarla-Marie naJain, 2015; Kanikarla-Marie na Jain, 2016). Zvakare, zvakakosha kufunga kuti iyo inoonekwa antioxidative bhenefiti inopihwa ne pleiotropic ketogenic dhayeti inogona kusatenderedzwa nemitumbi yemaketone ivo pachavo, uye neuroprotection inopihwa nemitumbi yemaketone inogona kunge isinganyanyo kuve nemhedzisiro yekushushikana nekushushikana. Semuenzaniso panguva yekushayikwa kweglucose, mune modhi yekushayikwa kweglucose mu cortical neurons,? OHB yakasimudzira kubuda kwemoto uye yakadzivirira kuunganidzwa kweopophagosome, iyo yaibatanidzwa nekuderera kwerufu kufa (Camberos-Luna et al., 2016). d-? OHB inokonzeresa zvakare canonical antioxidant mapuroteni FOXO3a, SOD, MnSOD, uye catalase, tarisiro kuburikidza neHDAC inhibition (Nagao et al., 2016; Shimazu et al., 2013).

Kwete-Kunwa Doro Zvisina Mwero Zvirwere Zvirwere (NAFLD) uye Ketone Body Metabolism

Kufutisa-kwakabatana NAFLD uye nonalcoholic steatohepatitis (NASH) ndizvo zvikonzero zvakanyanya zvechirwere chechiropa munyika dzekuMadokero (Rinella neSanyal, 2016), uye NASH-yakakonzera kutadza kwechiropa ndicho chimwe chezvikonzero zvakajairika zvekuisirwa chiropa. Nepo kunyanyisa kuchengetwa kwetriacylglycerols mu hepatocytes> 5% yehuremu hwechiropa (NAFL) yega isingakonzere kushomeka kwechiropa, kuwedzera kuri NAFLD muvanhu kunoenderana neiyo systemic insulin kuramba uye kuwedzera njodzi yerudzi rwechipiri chirwere cheshuga, uye zvinogona kubatsira kune pathogenesis chirwere chemwoyo uye chirwere chisingaperi cheitsvo (Fabbrini et al., 2; Targher et al., 2009; Targher naByrne, 2010). Maitiro epathogenic eNaFLD neNASH haana kunyatsonzwisiswa asi anosanganisira kusagadzikana kwehepatocyte metabolism, hepatocyte autophagy uye endoplasmic reticulum kushushikana, hepatic immune cell function, adipose tishu kuzvimba, uye systemic kuzvimba vapikisi (Fabbrini et al., 2013; Masuoka naChalasani, 2009 ; Targher et al., 2013; Yang et al., 2010). Perturbations yehydrohydrate, lipid, uye amino acid metabolism inoitika mukati uye zvinopa kufutisa, chirwere cheshuga, uye NAFLD muvanhu uye nemhando dzezvipenyu [yakadzokororwa mu (Farese et al., 2010; Lin naAccili, 2012; Newgard, 2011; Samuel na Shulman, 2012; Zuva naLazar, 2012)]. Kunyange hepatocyte isina kujairika mu cytoplasmic lipid metabolism inowanzoonekwa mu NAFLD (Fabbrini et al., 2013b), iro basa re mitochondrial metabolism, iro rinotonga kurasa kwemafuta emafuta harina kujeka mu NAFLD pathogenesis. Kusagadzikana kwemitochondrial metabolism kunoitika mukati uye kunopa NAFLD / NASH pathogenesis (Hyotylainen et al., 2010; Serviddio et al., 2016; Serviddio et al., 2011; Wei et al., 2008). Iko kune zvakajairika (Felig et al., 2008; Iozzo et al., 1974; Koliaki et al., 2010; Satapati et al., 2015; Satapati et al., 2015; Sunny et al., 2012) asi kwete yunifomu ( Koliaki naRoden, 2011; Perry et al., 2013; Rector et al., 2016) kubvumirana kuti, isati yagadziriswa NASH, hepatic mitochondrial oxidation, uye kunyanya mafuta oxidation, inowedzerwa mukufutisa, systemic insulin kuramba , uye NAFLD. Zvichida kuti sezvo NAFLD ichifambira mberi, oxidative kugona heterogenity, kunyangwe pakati peimwe mitochondria, inobuda, uye pakupedzisira oxidative basa rinokanganisa (Koliaki et al., 2010; Rector et al., 2015; Satapati et al., 2010; Satapati et al. ., 2008).

Ketogenesis inowanzo shandiswa se proxy ye hepatic fat oxidation. Kukanganisa kwe ketogenesis kubuda se NAFLD kufambira mberi mumhando dzemhuka, uye pamwe muvanhu. Kuburikidza nenzira dzisingatsanangurike, hyperinsulinemia inodzvinyirira ketogenesis, pamwe ichipa hypoketonemia kana ichienzaniswa neakaremara kutonga (Bergman et al., 2007; Bickerton et al., 2008; Satapati et al., 2012; Soeters et al., 2009; Sunny et al. , 2011; Vice et al., 2005). Kunyange zvakadaro, kugona kwekutenderera ketone kuwanda kwemuviri kufungidzira NAFLD kunokakavara (M nnist et al., 2015; Sanyal et al., 2001). Nzira dzakasimba dzemagineti resonance spectroscopic nzira mumhando dzemhuka dzakaratidza kuwedzera ketone chiyero cheyero ine mwero insulin kudzvinyirira, asi kudzikira kwemitengo kwaionekera nekuwedzera insulin insulin (Satapati et al., 2012; Sunny et al., 2010). Muvanhu vakafutisa vane mafuta echiropa, ketogenic chiyero chakajairika (Bickerton et al., 2008; Sunny et al., 2011), uye nekudaro, iwo mwero we ketogenesis wakadzikira maererano neakawedzera mafuta asidi mutoro mukati me hepatocytes. Nekudaro,? -Xidation-inotorwa acetyl-CoA inogona kuendeswa kune yekupedzisira oxidation muTCA kutenderera, kuwedzera terminal oxidation, phosphoenolpyruvate-inotyairwa gluconeogenesis kuburikidza neaplerlerosis / cataplerosis, uye oxidative kusagadzikana. Acetyl-CoA zvakare inogona kuenda kunze kwenyika kubva mitochondria se citrate, yekumberi substrate ye lipogenesis (Fig. 4) (Satapati et al., 2015; Satapati et al., 2012; Solinas et al., 2015). Ipo ketogenesis ichiva isinganyanyoteereri kune insulin kana kutsanya nekufutisa kwenguva refu (Satapati et al., 2012), maitiro ari pasi uye mhedzisiro yemhedzisiro yeiyi inoramba isina kunyatsonzwisiswa. Uchapupu hwazvino hunoratidza kuti mTORC1 inodzvinyirira ketogenesis nenzira inogona kunge iri pasi pekuratidzira kwe insulin (Kucejova et al., 2016), inoenderana nekucherechedza kuti mTORC1 inodzivisa PPAR? -Mediated Hmgcs2 induction (Sengupta et al., 2010) ( onawo Mutemo weHMGCS2 uye SCOT / OXCT1).

Pakutanga kucherechedzwa kubva kuboka redu zvinoratidza kukanganisika hepatic mhedzisiro yekushaya kukwana ketogenic (Cotter et al., 2014). Kuti tiongorore fungidziro iyo isina kukwana ketogenesis, kunyangwe mune makabhohydrate-akazara uye nekudaro non-ketogenic nyika, zvinopa kusajairika glucose metabolism uye kunotsamwisa steatohepatitis, isu takagadzira mbeva modhi yekucherechedza ketogenic kusakwana nekutungamirwa kweantisense oligonucleotides (ASO) yakanangwa Hmgcs2. Kurasikirwa kweHMGCS2 mune yakajairika yakaderera-mafuta chow-yakadyiwa mbeva dzevakuru dzakakonzera nyoro hyperglycemia uye zvakanyanya kuwedzera kugadzirwa kwemazana ehepatic metabolites, suite yeiyo yakanyatsoratidza lipogenesis activation. Kudya-kwemafuta kudya kudya kwemakonzo asina kukwana ketogenesis kwakakonzera kukuvara kukuru kwehepatocyte uye kuzvimba. Izvi zvakawanikwa zvinotsigira pfungwa dzepakati dzekuti (i) ketogenesis haisi nzira yekufashukira asi inzvimbo ine simba mune hepatic uye yakabatana yehupenyu homeostasis, uye (ii) kuchenjera ketogenic kuwedzera kudzikisira NAFLD / NASH uye kusagadzikana hepatic glucose metabolism inokodzera kuongorora .

Ketogenesis isina kunaka ingakonzera sei kukuvara kwechiropa uye nekuchinja glucose homeostasis? Chekutanga kufunga ndechekuti honzeri kushayikwa kwe ketogenic flux, kana ketoni ivo pachavo. Chirevo chazvino chinoratidza kuti ketone miviri inogona kudzora oxidative kusagadzikana-kwakakonzera kukuvara kwehepatic mukupindura n-3 polyunsaturated fatty acids (Pawlak et al., 2015). Yeuka kuti nekuda kwekushomeka kweCSOT kutaura mune hepatocytes, ketone miviri haina oxidized, asi inogona kubatsira kune lipogenesis, uye kushandira akasiyana siyana ekuratidzira mabasa akazvimiririra neiyo oxidation yavo (onawo Asina-oxidative metabolic mafeti emaketone miviri uye? OHB se murevereri anonongedza). Izvo zvakare zvinokwanisika kuti hepatocyte-yakatorwa ketone miviri inogona kushanda sechiratidzo uye / kana metabolite yemamwe maseru emhando mukati meiyo hepatic acinus, kusanganisira masero e stellate uye Kupffer maseru macrophages. Nepo mashoma mabhuku aripo anoratidza kuti macrophages haakwanise kuisa oxidize miviri ye ketone, izvi zvakangoyerwa uchishandisa echinyakare nzira, uye chete mu peritoneal macrophages (Newsholme et al., 1986; Newsholme et al., 1987), zvichiratidza kuti re- kuongorora kwakakodzera kwakapihwa kuwanda kweSCOT kutaura mumabhonzo-akatorwa macrophages (Youm et al., 2015).

Hepatocyte ketogenic flux inogona zvakare kuve cytoprotective. Kunyange nzira dzekukwazisa dzingangorega ketogenesis pa se, yakaderera makabhohaidhiretsi ketogenic kudya kunosanganisirwa nekusimudzira NAFLD (Browning et al., 2011; Foster et al., 2010; Kani et al., 2014; Schugar naCrawford, 2012) . Zvatinoona zvinoratidza kuti hepatocyte ketogenesis inogona kupindura uye kudzora TCA kutenderera kuyerera, anaplerotic flux, phosphoenolpyruvate-yakatorwa gluconeogenesis (Cotter et al., 2014), uye kunyange glycogen turnover. Ketogenic kuora mwoyo kunotungamira acetyl-CoA kuwedzera TCA kubuda, uko chiropa kwakabatanidzwa nekuwedzera kukuvara kweROS-Mediated (Satapati et al., 2015; Satapati et al., 2012); inomanikidza kuchinjaniswa kwekabhoni mu de novo synthesized lipid mhando dzinogona kuratidza cytotoxic; uye inodzivirira NADH re-oxidation kuNAD + (Cotter et al., 2014) (Fig. 4). Kutorwa pamwechete, kuyedzwa kweramangwana kunodiwa kugadzirisa nzira kuburikidza neiyo ketogenic kusakwana kunogona kuve kwakashata, kunopa hyperglycemia, kumutsa steatohepatitis, uye kana nzira idzi dzichishanda muvanhu NAFLD / NASH. Sezvo humbowo hwehutachiona hunoratidza kusakwana ketogenesis panguva yekufambira mberi kwe steatohepatitis (Embade et al., 2016; Marinou et al., 2011; M nnist et al., 2015; Pramfalk et al., 2015; Safaei et al., 2016) mishonga inowedzera hepatic ketogenesis inogona kuratidza salutary (Degirolamo et al., 2016; Honda et al., 2016).

Ketone Bodies uye Heart Failure (HF)

Nechiyero chemetaboli chinopfuura mazana mana kcal / kg / zuva, uye kuwanda kwe400 6 kg ATP / zuva, moyo ndiyo nhengo ine simba rekushandisa zvakanyanya uye kudiwa kweiyo oxidative (Ashrafian et al., 35; Wang et al., 2007b). Iyo yakawanda kwazvo myocardial simba kutendeuka kunogara mukati me mitochondria, uye 2010% yeichi chiwanikwa chinotangira kuFAO. Mwoyo unotenderera uye unochinjika pasi pemamiriro ezvinhu akajairika, asi moyo unogadziridza hutachiona (semuenzaniso, nekuda kwehypertension kana myocardial infarction) uye moyo weshuga wega wega unogadzikana (Balasse naFery, 70; BING, 1989; Fukao et al., 1954 ; Lopaschuk et al., 2004; Taegtmeyer et al., 2010; Taegtmeyer et al., 1980; Muduku et al., 2002). Chokwadi, genetically yakarongedzwa kusagadzikana kweiyo cardiac mafuta metabolism mune mbeva mhando zvinokonzeresa cardiomyopathy (Carley et al., 2002; Neubauer, 2014). Pasi pemamiriro ehupenyu zvakajairika moyo inosanganisa miviri ye ketone zvichienderana nekuburitswa kwayo, pamutero we fatty acid uye glucose oxidation, uye myocardium ndiyo yakanyanya ketone muviri mutengi pauniti hombe (BING, 2007; Crawford et al., 1954; GARLAND et al. ., 2009; Hasselbaink et al., 1962; Jeffrey et al., 2003; Pelletier et al., 1995; Tardif et al., 2007; Yan et al., 2001). Inofananidzwa nemafuta easidhi oxidation, miviri ye ketone inoshanda zvine simba, ichipa simba rakawanda rinowanikwa kuATP synthesis pamorekuru reoksijeni rakaiswa (P / O ratio) (Kashiwaya et al., 2009; Sato et al., 2010; Veech, 1995) . Ketone muviri oxidation zvakare inoburitsa inogona kunge iine simba rakakwira kupfuura FAO, ichichengeta ubiquinone oxidized, iyo inomutsa redox span muketani yekutakura yemagetsi uye inoita kuti simba rakawanda riwanikwe kugadzira ATP (Sato et al., 2004; Veech, 1995). Kuchengetedzwa kwemitumbi yeketone kunogona zvakare kudzora kugadzirwa kweROS, uye nekudaro kushushikana kweiyo oxidative (Veech, 2004).

Kutangira kwekupindira nekuongororwa kwekucherechedza kunoratidza kushandiswa kwemashoko ekugadzirisa miviri mumoyo. Muchiitiko chekuongorora ischemia / reperfusion mumamiriro ezvinhu ekukuvadza, miviri ye ketone inogadziriswa inogona kuitika pamagetsi (Al-Zaid et al., 2007; Wang et al., 2008), zvichida nekuda kwekuwedzera mitochondrial yakawanda mumoyo kana up-mutemo weiyo yakakosha phosphorylation vamiririri (Snorek et al., 2012; Zou et al., 2002). Zvidzidzo zvenguva pfupi zvinoratidza kuti ketone inoshandiswa muviri inowedzera mukukanganisa mwoyo yeveve (Aubert et al., 2016) nevanhu (Bedi et al., 2016), vachitsigira kutarisa kwevanhu kare (BING, 1954; Fukao et al., 2000; Janardhan et al., 2011; Longo et al., 2004; Rudolph naSchinz, 1973; Tildon uye Cornblath, 1972). Kupararira ketone muviri kuongororwa kunowedzera mumoyo kukanganisa varwere, zvakananga zvichienderana nekuzadza zvipingamupinyi, kutarisa maitiro uye kukosha hazvizivikanwe (Kupari et al., 1995; Lommi et al., 1996; Lommi et al., 1997; Neely et al ., 1972), asi makonzo ane kukwana kweSOTOT in cardiomyocytes inokurumidza kuwedzera pathological ventricular remodeling uye zvinyorwa zveROS mukupindira kwechiremera chinokonzerwa nechisimba chekuremedza (Schugar et al., 2014).

Zvakaitika munguva inotevera zvinonakidza mukurapa kwechirwere cheshuga zvakaratidza unogona kuwirirana pakati pe myocardial ketone metabolism uye pathological ventricular remodeling (Fig. 5). Kuvharidzirwa kwechirwere chinokonzerwa nehebular sodium / glucose co-transporter 2 (SGLT2i) inowedzera kupararira kweketone mumuviri wevanhu (Ferrannini et al., 2016a; Inagaki et al., 2015) uye mice (Suzuki et al., 2014) kuburikidza nekuwedzera hepatic ketogenesis (Ferrannini et al., 2014; Ferrannini et al., 2016a; Katz uye Leiter, 2015; Mudaliar et al., 2015). Zvichida, kamwechete yevashandi ava yakaderedza HF hospitalization (semuenzaniso, sezvakaratidzwa neEEM-REG OUTCOME trial), uye yakagadziriswa nemararamiro evanhu (Fitchett et al., 2016; Sonesson et al., 2016; Wu et al., 2016a ; Zinman et al., 2015). Kunyange zvazvo nzira yekufambisa inogadzirisa zvibereko zvakanaka zveHF zvekubatanidza SGLT2i inoramba ichiitirana nhaurirano, rubatsiro rwekuchengetedza runogona kunge rwakawanda, ruzhinji runosanganisira ketosis asiwo ruzivo rwehutachiona pamusoro pesero, ropa, glucose uye uric acid mazinga, kusagadzikana kwegadziriro, hurongwa hwekutya tsitsi, osmotic diuresis / kuderedza plasma volume, uye kuwedzera hematocrit (Raz naCahn, 2016; Vallon na Thomson, 2016). Zvakatorwa pamwechete, pfungwa yokuti kurapa ketonemia inotakura muHF varwere, kana avo vari pangozi yakakura yekukudziridza HF, inoramba ichikakavadzana asi iri pasi pekutsvakurudza kushandiswa kwezvakaitika kare uye kuchipatara zvidzidzo (Ferrannini et al., 2016b; Kolwicz et al., 2016; Lopaschuk uye Verma, 2016; Mudaliar et al., 2016; Taegtmeyer, 2016).

Ketone Bodies muCcercer Biology

Kuwirirana pakati pemaketone nemakumbo zvinokurumidza kubuda, asi zvidzidzo zvezvipfuwo zvose uye vanhu zvakagumisa zvirevo zvakasiyana. Nokuti ketone metabolism inosimba uye mamiriro ezvemuviri anoteerera, inonyengedza kutevera hupenyu hwehutano nekenza nekuda kwekugona kwehutano hwakatungamirirwa zvakanaka. Masero eC Cancer anotengesa kushandiswa kwemagetsi kuitira kuti varambe vachikurumidza kushandiswa kwesero nekukura (DeNicola naCanley, 2015; Pavlova na Thompson, 2016). Chikoro cheWarburg chinokonzerwa nemuchirwere chemetabolism chinokonzerwa nebasa guru re glycolysis uye lactic acid fermentation kuendesa simba uye kubhadhara kuderera kwakaderera phosphorylation yeiyo oxidative uye kupera kwemitochondrial shoma (De Feyter et al., 2016; Grabacka et al., 2016; Kang et al., 2015; Poff et al., 2014; Shukla et al., 2014). Glucose carbon inonyanya kunyoreswa kuburikidza ne glycolysis, pentose phosphate pathway, uye lipogenesis, iyo pamwe chete inopa zvikamu zvakakosha kuti chiremera chinokonzerwa nekemukari (Grabacka et al., 2016; Shukla et al., 2014; Yoshii et al., 2015). Kugadziriswa kwekenza masero kuti glucose inopera inowanikwa kuburikidza nekwanisi kushandisa zvimwe zvinotakura mafuta, kusanganisira acetate, glutamine, uye aspartate (Jaworski et al., 2016; Sullivan et al., 2015). Semuenzaniso, kusabvumirwa kusvika kune pyruvate kunoratidza kukwanisa kwekenza masero kuchinja glutamine mu-acetyl-CoA ne carboxylation, kuchengeta zvose simba uye anabolic zvinodiwa (Yang et al., 2014). Chimwe chinonakidza kugadziriswa kwekenza masero ndiko kushandiswa kweacetate semafuta (Comerford et al., 2014; Jaworski et al., 2016; Mashimo et al., 2014; Wright naSimone, 2016; Yoshii et al., 2015). Acetate isiriwo substrate ye lipogenesis, iyo inonyanya kukosha kumarara kwechiremera chekuita, uye kuwanikwa kwechirwere ichi chechipogenic kunobatanidza nekurarama kwenguva refu kwevarwere uye mutoro unorema (Comerford et al., 2014; Mashimo et al., 2014; Yoshii et al ., 2015).

Asina-gomarara maseru anoshandura simba ravo kubva pashuga kuenda mumitumbi yeketone panguva yeglucose kushomeka. Ipurasitiki iyi inogona kunge ichisiyana pakati pemhando dzekenza maseru, asi mu vivo yakaisirwa matumire ehuropi akaomeswa [2,4-13C2] -? OHB kusvika padanho rakafanana seyakaipoteredza matishu ehuropi (De Feyter et al., 2016). EverReverse Warburg athari kana maviri makamuri tumota metabolism - mhando dzinofungidzira kuti gomarara maseru anokonzeresa? OHB kugadzirwa padhuze nefibroblast, ichipa bundu remasero emagetsi (Bonuccelli et al., 2010; Martinez-Outschoorn et al., 2012) . Muchiropa, kuchinja kwe hepatocytes kubva ku ketogenesis kuenda kune ketone oxidation mu hepatocellular carcinoma (hepatoma) masero anoenderana nekumisikidza kweBDH1 uye SCOT zviitiko zvinoonekwa mune mbiri hepatoma maseru mitsara (Zhang et al., 1989). Chokwadi, maseru ehepatoma anoratidza OXCT1 uye BDH1 uye oxidize ketoni, asi chete kana serum yakafa nenzara (Huang et al., 2016). Neimwe nzira, bundu sero ketogenesis yakagadziridzwawo. Kuchinja kwesimba mu ketogenic gene expression kunoratidzwa panguva yekenza kushandurwa kwecolonic epithelium, sero mhando iyo inowanzo kuratidza HMGCS2, uye mushumo uchangobva kuitika wakaratidza kuti HMGCS2 inogona kunge iri chiratidzo chekufungidzira kwakashata mune colorectal uye squamous cell carcinomas (Camarero et al., 2006; Chen et al., 2016). Kunyangwe kushamwaridzana uku kuchida kana kunosanganisira ketogenesis, kana basa rekujekesa mwedzi reHMGCS2, rinoramba richigadziriswa. Zvakare, zviri pachena? OHB kugadzirwa nemelanoma uye glioblastoma maseru, akakurudzirwa nePARAR? agonist fenofibrate, yaibatanidzwa nekukura kusungwa (Grabacka et al., 2016). Zvimwe zvidzidzo zvinotarisirwa kuratidza mabasa eHMGCS2 / SCOT expression, ketogenesis, uye ketone oxidation mumasero ekenza.

Kunze kwenzvimbo yemafuta emetabolism, maketoni achangobva kuverengerwa mukenza cell biology kuburikidza nechiratidzo chiratidzo. Kuongororwa kweBRAF-V600E + melanoma yakaratidza OCT1-inoenderana induction yeHMGCL mune oncogenic BRAF-inoenderana nenzira (Kang et al., 2015). HMGCL kuwedzera kwaive kwakabatana neakakwira maseru AcAc yevasungwa, iyo yakasimudzira kudyidzana kweBRAFV600E-MEK1, ichiwedzera chiratidzo cheMEK-ERK mune yekudyira-yekumberi chiuno chinotyaira bundu sero kukura uye kukura. Aya macherechedzo anomutsa mubvunzo unokatyamadza weanotarisira extrahepatic ketogenesis iyo inotsigira nzira yekuratidzira (onawo OHB semurevereri wekuratidzira neMakakatanwa mu extrahepatic ketogenesis). Izvo zvakakoshawo kuti utarise yakazvimirira mhedzisiro yeAcAc, d-? OHB, uye l- OHB pane cancer metabolism, uye kana uchifunga nezveHMGCL, leucine catabolism inogona zvakare kupenga.

Mhedzisiro yezvikafu zve ketogenic (onawo Kurapa kwekushandisa kwe ketogenic kudya uye exogenous ketone miviri) mune kenza mhuka mhando dzakasiyana (De Feyter et al., 2016; Klement et al., 2016; Meidenbauer et al., 2015; Poff et al. ., 2014; Seyfried et al., 2011; Shukla et al., 2014). Nepo masangano eepidemiological pakati pekufutisa, gomarara, uye ketogenic kudya kunopikiswa (Liskiewicz et al., 2016; Wright naSimone, 2016), meta-ongororo ichishandisa ketogenic chikafu mune mhando dzemhuka uye muzvidzidzo zvevanhu zvakaratidza musaruro pesvedzero pakurarama, ne mabhenefiti anotariswa zvakabatana nehukuru hwe ketosis, nguva yekutanga kudya, uye nzvimbo yemarara (Klement et al., 2016; Woolf et al., 2016). Kurapa kwepancreatic cancer maseru ane ketone miviri (d-? OHB kana AcAc) yakadzivirira kukura, kuwanda uye glycolysis, uye ketogenic kudya (81% kcal mafuta, 18% protein, 1% carbohydrate) yakaderedzwa mu vivo tumota huremu, glycemia, uye yakawedzera mhasuru uye uremu hwemuviri mumhuka dzine kenza yakaisirwa (Shukla et al., 2014). Mhedzisiro yakafanana yakaonekwa uchishandisa metastatic glioblastoma cell modhi mumakonzo akagamuchira ketone yekuwedzera mune yekudya (Poff et al., 2014). Zvakare, chikafu che ketogenic (91% kcal mafuta, 9% protein) yakawedzera kutenderera? OHB kusangana uye kudzikira glycemia asi haina kana chinetso pane bundu vhoriyamu kana kupona kwenguva mumakonzo anotakura glioma (De Feyter et al., 2016). Chiratidzo cheglucose ketone chakarondedzerwa sechiratidzo chekiriniki icho chinovandudza manejimendi manejimendi ehutachiona hwehutachiona hwehutachiona muhutachiona hwehutachiona muvanhu nemakonzo (Meidenbauer et al., 2015). Kutorwa pamwechete, mabasa emaketone muviri metabolism uye ketone miviri mukenza biology iri kunakidza nekuti imwe neimwe ine nzira dzinotakurika dzokurapa, asi zvakakosha zvinhu zvinoramba zvichitsanangurwa, zvine simba rakajeka rinobuda kubva mumatrix ezvimwe zvinosanganisa, kusanganisira (i) misiyano pakati peakanyanya ketone miviri inopesana neketogenic kudya, (ii) cancer cancer mhando, genomic polymorphisms, giredhi, uye nhanho; uye (iii) nguva uye nguva yekuratidzwa kune iyo ketotic nyika.

Ketogenesis yakaumbwa nemitumbi miviri kuburikidza nekudengenyeka kwemafuta acid uye ketogenic amino acids. Iyi nzira yehupenyu hwechimiro inopa simba kune nhengo dzakasiyana-siyana, kunyanya uropi, pasi pemamiriro ezvinhu ekutsanya semhinduro kumusana kweropa glucose. Zvitunha zveKetone zvinowanzobudiswa mitochondria yemasero eropa. Kunyange zvazvo mamwe masero ari kukwanisa kuita ketogenesis, haasi ezvo pakuita saizvozvo semasero eropa. Nokuti ketogenesis inowanikwa mu mitochondria, zvayo zvinotungamirirwa zvakasununguka. Dr. Alex Jimenez DC, CCST Insight

Kucherechedza Kushandiswa kweKetogenic Zvokudya uye Zvimwe Zvimwe zveKetone

Iko kushandiswa kwezvikafu zve ketogenic nemitumbi yeketone semidziyo yekurapa yakamukawo mune zvisiri zvekenza zvinosanganisira kufutisa uye NAFLD / NASH (Browning et al., 2011; Foster et al., 2010; Schugar naCrawford, 2012); kutadza kwemoyo (Huynh, 2016; Kolwicz et al., 2016; Taegtmeyer, 2016); neurological uye neurodegenerative chirwere (Martin et al., 2016; McNally naHartman, 2012; Rho, 2015; Rogawski et al., 2016; Yang naCheng, 2010; Yao et al., 2011); zvikanganiso zvekuzvarwa zvemetabolism (Scholl-B rgi et al, 2015); uye kurovedza muviri kuita (Cox et al., 2016). Kubudirira kwezvikafu zve ketogenic kwave kuchinyanya kukosheswa pakurapa kwekugumburwa kwechirwere, kunyanya mune varwere vasingagone kushandisa zvinodhaka. Zvizhinji zveongororo zvakaongorora ketogenic yekudya muvarwere vevana, uye zvinoratidza kusvika ku ~ 50% kudzikisira mukutora nguva mushure memwedzi mitatu, pamwe nekuvandudzwa kwekuita musarudzo syndromes (Wu et al., 3b). Chiitiko ichi chinogumira muvanhu vakuru pfari, asi kudzikiswa kwakafanana kuri pachena, nemhinduro iri nani muzviratidzo zvevarwere vane pfari (Nei et al., 2016). Maitiro epasi ekurwisa-kusagadzikana anoramba asina kujeka, kunyangwe akaiswa mafungiro anosanganisira kudzikisira glucose kushandiswa / glycolysis, kugadziriswazve kutakurwa kwegutamate, kukanganisa kwakanangana neATP-inonzwisisika potassium chiteshi kana adenosine A2014 receptor, shanduko yesodium chiteshi isoform expression, kana mhedzisiro pakutenderera kwehomoni kusanganisira leptin ( Lambrechts et al., 1; Lin et al., 2016; Lutas naYellen, 2017). Zvinoramba zvisina kujeka kana iyo inorwisa-kushushikana mhedzisiro inonyanya kukonzerwa nemitumbi yemaketone, kana nekuda kwemhedzisiro yemhedzisiro mhedzisiro yezvakaderera zvehydrohydrate kudya Kunyange zvakadaro, ketone esters (ona pazasi) inoita kunge inosimudzira chikumbaridzo chekutora mumhando dzemhuka dzekugumburwa (Ciarlone et al., 2013; D'Agostino et al., 2016; Viggiano et al., 2013).

Atkins-style uye ketogenic, zvishoma neyakakodhiyidhariti zvinowanzoonekwa zvisina kufadza, uye zvinogona kukonzera kubatwa, hyperuricemia, hypocalcemia, hypomagnesemia, inotungamirira nephrolithiasis, ketoacidosis, inokonzera hyperglycemia, uye inosimudza cholesterol nemafuta emafuta asirikidza (Bisschop et al., 2001 ; Kossoff naHartman, 2012; Kwiterovich et al., 2003; Suzuki et al., 2002). Nokuda kwezvikonzero izvi, kuratidzira kwenguva refu kunowedzera zvinetso. Zvidzidzo zvehutano zvinowanzoshandisa kushandiswa kwema macronutrient (94% kcal mafuta, 1% kcal carbohydrate, 5% kcal protein, Bio-Serv F3666), iyo inokonzera ketosis yakasimba. Zvisinei, kuwedzera mapuroteni anokwana, kunyange ku10% kcal inowedzera kukonzera ketosis, uye 5% kcal protein kudzivirira inopesanisa kusagadzikana kwemagetsi nemafuta. Izvi zvinogadziriswa zvekare zvekudya zvakashata, imwe shanduko inokonzera kukanganisa kukuvadzwa kwechiropa, uye kunyange ketogenesis (Garbow et al., 2011; Jornayvaz et al., 2010; Kennedy et al., 2007; Pissios et al., 2013; Schugar et al., 2013). Migumisiro yenguva yakareba yekudya kwemakemikari mumashonga inoramba isina kunyatsotsanangurwa, asi zvidzidzo zvenguva pfupi mutsva zvakaratidza kupona kwemazuva ose uye kusavapo kwekukuvadza kwechiropa mukati mutsva pamitambo ye ketogenic pamusoro pemararamiro avo, kunyange zvazvo amino acid metabolism, kushandiswa kwesimba, uye zviratidzo zve insulini zvakanyorwa zvakanyorwa (Douris et al., 2015).

Nzira dzekuwedzera ketosis kuburikidza nenzira dzinoshandiswa pakudya kwekotogenic dzinosanganisira kushandiswa kwegadziriro dzisingagoni kushandiswa muviri. Kutungamirirwa kwemasikirini emaketone akadai kunogona kusimbisa humwe hutano hwakasiyana hwakasangana nehutano hwepanyama, nokuti kuparadzanisa glucose uye insulin zvinowanzoitika, asi masero anogona kuita kuti glucose isagadziriswe uye kushandiswa. Mitumbi yeKetone pachawo ine mapfupi hafu-ehupenyu, uye kumedzwa kana kuiswa kwe sodium? OHB munyu kuti uwane kurapa ketosis inokonzeresa untoward sodium mutoro. R / S-1,3-butanediol isiri-chepfu dialcohol iyo iri nyore oxidized muchiropa kuburitsa d / l-? OHB (Desrochers et al., 1992). Mune mamiriro akasarudzika ekuyedza, muyero uyu wakapihwa zuva nezuva kumakonzo kana makonzo kwenguva yakareba sevhiki nomwe, zvichipa kutenderera? OHB kuwanda kusvika kusvika 5 mM mukati me2 h yekutonga, iyo yakagadzikana kweinenge yakawedzera 3h (D ' Agostino et al., 2013). Kuparadzaniswa kwezvokudya zvekudya kwakave kwakaratidzwa mumakonzo anopiwa R / S-1,3-butanediol (Carpenter naGrossman, 1983). Uye zvakare, matatu emakemikari akasarudzika ketone esters (KEs), (i) monoester yeR-1,3-butanediol uye d-? OHB (R-3-hydroxybutyl R-? OHB); (ii) glyceryl-tris-? OHB; uye (iii) R, S-1,3-butanediol acetoacetate diester, akave akaongororwa zvakanyanya (Brunengraber, 1997; Clarke et al., 2012a; Clarke et al., 2012b; Desrochers et al., 1995a; Desrochers et al. ., 1995b; Kashiwaya et al., 2010). Chinhu chinobatika chekutanga ndechekuti 2 mamota ehupenyu d- OHB inogadzirwa pamore rimwe reKE, zvichitevera esterase hydrolysis mumatumbo kana chiropa. Kudzivirirwa, pharmacokinetics, uye kushivirira zvakave zvakadzidzwa zvakanyanya muvanhu vachidya R-3-hydroxybutyl R-? OHB, pamadosi anosvika ku714 mg / kg, kuburitsa kutenderera d-? OHB kukosheswa kusvika 6 mM (Clarke et al., 2012a; Cox et al., 2016; Kemper et al., 2015; Shivva et al., 2016). Mumakondohwe, izvi KE inoderedza caloric kudya uye plasma cholesterol yakawanda, inosimudzira maronda adipose, uye inovandudza insulin kudzivisa (Kashiwaya et al., 2010; Kemper et al., 2015; Veech, 2013). Zvakawanikwa munguva pfupi yapfuura zvinoratidza kuti panguva yekurovedza muviri muvatambi vakarovedzwa, R-3-hydroxybutyl R-? OHB kumedza kwakadzora tsandanyama tsandanyama glycolysis uye plasma lactate kuwanda, yakawedzera intramuscular triacylglycerol oxidation, uye yakachengetedza tsandanyama glycogen zvemukati, kunyangwe kana co-ingested carbohydrate yakasimudzira insulin secretion ( Cox et al., 2016). Kuwedzerwa mberi kwekuvandudzwa kwezviitiko izvi zvinonakidza zvinodikanwa, nokuti kuvandudzwa kwekutsungirira kwekuita basa kwakanyanya kunotungamirirwa nemhinduro yakasimba kune KE mune 2 / 8 zvidzidzo. Kunyange zvakadaro, izvi zvinowanikwa zvinotsigira zvidzidzo zvechikoro zvinoratidza kusarudza ketone oxidation pane mamwe mashizha (GARLAND et al., 1962; Hasselbaink et al., 2003; Stanley et al., 2003; Valente-Silva et al., 2015), kusanganisira panguva yekurovedza muviri, uye kuti vatambi vakarovedzwa vangave vakakurudzirwa kushandisa maketoni (Johnson et al., 1969a; Johnson naWalton, 1972; Winder et al., 1974; Winder et al., 1975). Pakupedzisira, nzira dzinogona kusimbisa hutano hunovandudzwa hunoenderana nekuenzana kwema caloric kudya (kusiyana kwakasiyana pakati pe macronutrients) uye yakaenzana neyeroji yekushandiswa kwemitengo inoramba ichigadziriswa.

Ramangwana Maonero

Pane imwe nguva yakashurikidzwa senzira yekufashukira inokwanisa kuunganidza huturu hunobuda kubva mumafuta anopisa mumakabohydrate anotadzisa nyika (iyo ketotoxic paradigm), kucherechedzwa kwazvino kunotsigira pfungwa yekuti ketone body metabolism inosarudzika mabasa kunyangwe mune makabhohydrate-akazara nyika, kuvhura ketohormetic fungidziro. Ipo machira ekusovha uye ekushongedzerwa kwemakemikari ekushandisa ketone metabolism ichiita chinokwezva chekurapa, zvine hukasha zvichitsvaga asi zviyero zvine hungwaru zvinoramba zviri mune ese ekutanga uye ekushandura marabhorabhoritari. Unmet zvinodiwa zvabuda mumatunhu ekutsanangura iro basa rekusimbisa ketone metabolism mukushaya moyo, kufutisa, NAFLD / NASH, mhando 2 chirwere cheshuga, uye gomarara. Iko kukura uye kukanganisa kwe'asina-canonical 'anoratidzira mabasa emaketone miviri, kusanganisira kudzora kwePTMs izvo zvingangodzosera kumashure uye mberi munzira dzemagetsi uye dzinoratidzira, zvinoda kuongorora kwakadzama. Chekupedzisira, extrahepatic ketogenesis yaigona kuvhura inonakidza paracrine uye autocrine siginecha nzira uye nemikana yekukonzeresa kubatana-metabolism mukati meiyo nervous system uye mamota kuti uwane ekurapa magumo.

Kutenda

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

Mashoko Omuzasi

Ncbi.nlm.nih.gov

Mukupedzisa, miviri ye ketone inogadzirwa nechiropa kuitira kuti ishandiswe sosi yesimba kana pasina glucose yakakwana inowanika nyore mumuviri wemunhu. Ketogenesis inoitika kana paine mashoma eglucose mazinga muropa, kunyanya mushure mekunge mamwe maseru macarhydrate zvitoro apera. Chinangwa chechinyorwa chiri pamusoro apa chaive chekukurukura nezve akasiyana-siyana mativi emaketone miviri mumafuta emetabolism, kuratidza, uye kurapwa. Chiyero cheruzivo rwedu chinogumira kuchiropractic uye musana nyaya dzehutano. Kuti ukurukure nyaya yacho, ndapota inzwa wakasununguka kubvunza Dr. Jimenez kana kutibata nesu pa us915-850-0900 .

Yakarongedzwa naDkt Alex Jimenez

Inotsanangurwa kubva ku: Ncbi.nlm.nih.gov/pmc/articles/PMC5313038/

Yokuwedzera Nhaurirano Kukurukurirana: cAcute Back Pain

Kutambudzika shureIchi ndicho chimwe chezvikonzero zvakanyanya zvehurema uye nemazuva akarasika pabasa pasirese. Kutambudzika kwekuseri kunopa kune chechipiri chikonzero chakajairika chekushanyirwa kwehofisi yechiremba, kuwanda chete nehutachiona hwepamusoro-hwekufema. Vanenge makumi masere muzana muzana yevagari vachasangana nemarwadzo ekudzokera shure kamwechete muhupenyu hwavo Iyo musana chivakwa chakaomarara chakaumbwa nemapfupa, majoini, mitsipa, uye mhasuru, pakati pezvimwe zvinyoro. Kukuvara uye / kana mamiriro akawedzeredzwa, sengeherniated discs, inogona kupedzisira yaunza zviratidzo zvekurwadziwa kumashure. Kukuvara kwemitambo kana kukuvara kwetsaona yemotokari kazhinji ndizvo zvinowanzo kukonzera chikonzero chekurwadziwa kumashure, zvisinei, dzimwe nguva kufamba kwakareruka kunogona kuve nemhedzisiro inorwadza. Neraki, dzimwe nzira dzekurapa, senge chiropractic kuchengetedza, dzinogona kubatsira kudzikamisa marwadzo ekumusana kuburikidza nekushandiswa kwespinal kugadziridzwa uye manyorerwo ekugadzirisa, pakupedzisira kugadzirisa marwadzo ekurwadziwa.

EXTRA EXTRA | NHAURWA INOKOSHA: Yakakurudzirwa El Paso, TX Chiropractor

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