Cholesterol biosynthesis le biochemistry ea eona - Lefu la tsoekere
Ntle ho pelaelo, k'holeseterole ke eona lipid e tsebahalang ka ho fetisisa ho sechaba ka kakaretso; e tsebahala ka lebaka la kamano e phahameng lipakeng tsa cholesterol e phahameng ea mali le khafetsa mafu a pelo le methapo. Ho sa tsotelloe ka hloko karolo e bohlokoa ea k'holeseterole e le karolo ea likarolo tsa lisele le e le selelekela sa li-hormone tsa steroid le li-acid acid. Cholesterol e hlokahala bakeng sa liphoofolo tse ngata, ho kenyelletsa le batho, empa boteng ba eona lijong tsa liphoofolo tse anyesang ke boikhethelo - lisele tsa 'mele ka botsona li ka e kopanya ho tsoa ho tse tlilleng pele ho nako.
Sebopeho sa k'homphieutha ena ea khase e 27 se bontša tsela e rarahaneng bakeng sa biosynthesis ea eona, empa liathomo tsohle tsa eona tsa khabone li fanoa ke mothehi a le mong - acetate. Libaka tsa Isoprene - lipakeng tsa bohlokoa ka ho fetisisa tse tsoang ho acetate ho ea k'holeseterole, ke tsona tse tlang pele ka lipids tse ngata tsa tlhaho, 'me mehato eo li-blockpies tsa isoprene li tsamaeang ka polymer li tsoana le tseleng tsohle tsa metabolic.
Re qala ka ho hlahloba methati e meholo tseleng ea cholesterol biosynthesis ho tloha acetate, ebe re buisana ka ho tsamaisoa ha k'holeseterole ho tsoa maling, ho kenella ha eona ka lisele, molao o tloaelehileng oa kolesterol, le taolo ea ho koaloa kapa ho tsamaisoa ha bobebe. Ebe re sheba lintho tse ling tse tsoang k'holeseterole, tse kang li-acid acid le lihomone tsa steroid. Kamora nako, litlhaloso tsa mekhoa ea biosynthetic ea ho theha metsoako e mengata - melemo ea lithibelo tsa isoprene, eo ho eona ho nang le mekhahlelo ea pele ea cholesterol, e tla bonts'a phapang e makatsang ea isoprenoid conduction ho biosynthesis.
Cholesterol e hlahisoa ho tsoa acetyl-CoA ka mekhahlelo e mene
Cholesterol, joalo ka li-acids tse telele tsa ketane, li entsoe ka acetyl-CoA, empa sebopeho sa kopano se fapane ka ho felletseng. Litekong tsa pele, acetate e ngotsoeng ka 14 C ebang ho atomyl kapa carboxyl carbon e ile ea eketsoa hore e fepe liphoofolo. Ho ipapisitsoe le phepelo ea lengolo la k'holeseterole e arotsoeng ho lihlopha tse peli tsa liphoofolo (sa feiga. 21-32), likarolo tsa enzymatic tsa cholesterol biosynthesis li hlalositsoe.
Sa feiga. 21-32. Mohloli oa liathomo tsa k'habone tsa k'holeseterole. E khethiloe nakong ea liteko tse sebelisoang radioactive acetate e ngotsoeng le methyl kh'ofi (e ntso) kapa carboxyl kh'ofi (khubelu). Ka sebopeho se emisitsoeng, mehele e hlalosoa ka litlhaku A ho D.
Mokhoa ona o etsahala ka mekhahlelo e mene, joalo ka ha o bonts'itsoe ho feiga. 21-33: (1) phumants'o ea masala a acetate a mararo ho etsa mokokotlo oa li-carbon tse tšeletseng tsa mevalonate, (2) phetoho ea mevalonate ho li-block tsa isoprene tse ts'ebetsong, (3) polymerization ea li-isopren tse nang le lik'habone tse hlano ho etsa mokokotlo oa li-squalene tse 30, (4) cyclization ea squalene. mehele e mene ea li-nucleus tsa steroid, e lateloang ke letoto la liphetoho (oxidation, ho tlosoa kapa ho falla ha lihlopha tsa methyl) ka ho etsoa ha cholesterol.
Sa feiga. 21-33. Setšoantšo se akaretsang sa cholesterol biosynthesis. Mehato e mene ea kenyelletso e tšohloa temeng. Li-block tsa Isoprene ka squalene li tšoauoa ka mela e khubelu e senyehileng.
Mothati (1). Synthesis ea mevalonate ho tloha acetate. Mokhahlelo oa pele oa cholesterol biosynthesis o lebisa ho thehoeng ha sehlahisoa se mahareng mellonate (Sa feiga 21-34). Limolek'hule tse peli tsa acetyl CoA li lumellana le ho fa acetoacetyl CoA, e lumellanang le molek'hule oa acetyl CoA ea boraro ho theha motsoako oa li-carbon tse tšeletseng β-hydroxy-β-methylglutaryl-CoA (HM G -CoA). Liphetoho tsena tse peli tsa pele li ts'oarehile thiolase le NM G -CoA synthase, ka ho latellana. Cytosolic NM G-CoA synthase Tsela ena ea metabolic e fapana le mitochondrial isoenzyme, e thusang motsoako oa NM G -CoA nakong ea sebopeho sa 'mele oa ketone (bona sa feiga. 17-18).
Sa feiga. 21-34. Sebopeho sa mevalonate ho tloha acetyl-CoA. Mohloli oa C-1 le C-2 mevalonate ho tloha acetyl-CoA o totobalitsoe ka pinki.
Boitšoaro ba boraro bo fokotsa lebelo la ts'ebetso eohle. Ho eona, NM G -CoA e fokotseha hore e be mevalonate, eo e ngoe le e ngoe ea limolek'hule tse peli tsa NUE D PH e fanang ka li-elektrone tse peli. HMG-CoA reductase - protheine ea bohlokoa ea membrane ea ER e boreleli, ea sebeletsa, joalo ka ha re tla bona hamorao, e le ntlha ea mantlha ea taolo ea tsela ea metabolic ea sebopeho sa cholesterol.
Mothati (2). Ho fetoloa ha mevalonate hore e be isopren e sebetsang habeli. Boemong bo latelang ba motsoako oa cholesterol, lihlopha tse tharo tsa phosphate li fetisoa ho tloha limolek'hule tsa ATP li fetoloa mevalonate (sa feiga. 21-35). Phosphate e tlameletsoe ho sehlopha sa hydroxyl ho C-3 mevalonate bohareng ba 3-phospho-5-pyrophosphomevalonate ke sehlopha se setle sa ho tloha, mohato o latelang ka bobeli ba li-phosphates le sehlopha se haufi sa carboxyl se tloha, se theha maqhama a mabeli ho sehlahisoa sa khabone ea bohlano ∆ 3 -isopentenyl pyrophosphate. Ena ke ea pele ho tse peli tse sebetsang tsa isoprenes - barupeluoa ba ka sehloohong ho kenyelletsong ea k'holeseterole. Isomerization ea Δ 3 -isopentenylpyrophosphate e fana ka isopren ea bobeli e sebetsang dimethylallyl pyrophosphate. Tsela ea isopentenyl pyrophosphate ho cytoplasm ea lisele tsa limela e etsahala ho latela tsela e hlalositsoeng mona. Leha ho le joalo, li-chloroplasts tsa semela le libaktheria tse ngata li sebelisa tsela e ikemetseng ea mevalonate. Mokhoa ona o mong ha o fumanehe ho liphoofolo, ka hona oa ho khahla ha o theha lithibela-mafu tse ncha.
Sa feiga. 21-35. Phetohelo ea mevalonate ho li-block tsa isoprene tse kenngoeng. Diyuniti tse tsheletseng tse kopantsoeng li kopana ho theha squalene (bona Setšoantšo sa 21-36). Lihlopheng tse tlohang tsa 3-phospho-5-pyrophosphomevalonate li totobalitsoe ka pinki. Mo mabekeng a lisekoere ke mohopolo o bohareng oa maikutlo.
Mothati (3). Chelete ea likarolo tse ts'eletseng ea isopren ho etsa squalene. Isopentenyl pyrophosphate le dimethylallyl pyrophosphate joale e feta tlasa mookotaba-hloohong, moo sehlopha se le seng sa pyrophosphate se sisinyehang le liforomo tse 10 tsa khabone - geranyl pyrophosphate (Sa feiga 21-36). (Pyrophosphate e latela hlooho.) Geranyl pyrophosphate e kenella phetolelong e latelang ea mohatla o nang le isopentenyl pyrophosphate, le liforomo tse 15 tsa carbon tse bohareng farnesyl pyrophosphate. Qetellong, limolek'hule tse peli tsa farnesyl pyrophosphate li kopanya "hloohong ho ea", lihlopha tsena ka bobeli tsa phosphate lia tlosoa - li thehiloe squalene.
Sa feiga. 21-36. Sebopeho sa squalene. Sebopeho sa squalene se nang le liathomo tsa khabone tse 30 se etsahala nakong ea li-concensation tse latellanang tse ntlafalitsoeng ke li-isoprene (li-kabone tse hlano).
Mabitso a tloaelehileng bakeng sa maele ana a tsoa ho mabitso a mehloli eo a neng a qheletsoe ho eona pele. Geraniol, e leng motsoako oa oli ea rose, e na le monko oa geranium, 'me farnesol, e fumanoang mebala ea acacia farnesa, e na le bohla ba monko oa phula. Monko o mengata oa limela tsa tlholeho ke oa likhomphutha tse hahiloeng ho li-isopren block. Squalene, ea pele e arotsoe ho sebete sa shark (Mefuta ea squalus), e na le liathomo tsa khabone tse 30: liathomo tse 24 ka ketane ea mantlha le liathomo tse tšeletseng tse kenngoeng ka tšepe.
Mothati (4). Phetoho ea squalene hore e be mehele e mene ea li-nucleid tsa steroid. Mofung. 21-37 ho bonahala ka ho hlaka hore sebopeho sa ketane ea squalene, le li-sterols - cyclic. Li-sterol tsohle li na le mehele e mene e tlotsitsoeng e etsang mookotaba oa steroid, 'me kaofela ke li-alcohols tse nang le sehlopha sa hydroxyl atomong ea C-3, ka hona lebitso la Senyesemane sterol. Tlas'a ketso squalene monoo oxygenase atom e le 'ngoe ea oksijene e tsoang O e eketsoa qetellong ea ketane ea squalene 2 mme epoxide ea thehoa. Enzyme ena ke oxidase e 'ngoe e tsoakiloeng e sebetsang (eketsa 21-1), NADPH e fokotsa atomo e' ngoe ea oksijene e tsoang ho O 2 ho H2 O. Lihlahisoa tsa Double Product squalene-2,3-epoxide E hlophisitsoe e le hore karabelo e lumellanang ka mokhoa o hlollang e ka fetolela mokokotlo oa squalene epoxide hore e be sebopeho sa potoloho. Liseleng tsa liphoofolo, cyclization ena e lebisa popong ea lanosterol e nang le mehele e mene ea tšebeliso ea li-nucleus tsa steroid. Ka lebaka leo, lanosterol e fetoloa k'holeseterole ka makhetlo a ka bang 20, e kenyelletsang ho falla ha lihlopha tse ling tsa tšepe le ho tlosoa ha ba bang. Tlhaloso ea tsela ena e hlollang ea biosynthesis, e 'ngoe e thata haholo har'a tse tsejoang, e entsoe ke Conrad Bloch, Theodore Linen, John Cornfort le George Popiak ho elella bofelong ba bo-1950.
Sa feiga. 21-37. Ho koaloa ha mehala ho fetola squalene ea mohala hore e be ntho e lumelletsoeng ea steroid. Mokhahlelo oa pele o ts'oaroa ke oxidase e nang le ts'ebetso e tsoakiloeng (monoo oxygenase), eo cosubstrate ea eona e leng N AD PH. Sehlahisoa ke epoxide, eo mohatong o latelang e tlang ho theha motheo oa steroid. Moetso oa hoqetleha oa liphetoho tsena liseleng tsa liphoofolo ke cholesterol; liseleng tse ling tsa limela li fapana haholo le tsona.
Cholesterol ke tšobotsi ea mofuta oa lisele tsa liphoofolo, limela, li-fungus le bo-ralitaba ba hlahisa li-sterols tse ling tse tšoanang haholo.
Ba sebelisa tsela e tšoanang ea squalene-2,3-epoxide, empa litsela li kheloha hanyane, ebe li-sterols tse ling li joalo ka sigmasterol lijalong tse ngata le ergosterol ka fungi (sa feiga. 21-37).
Mohlala Litsenyehelo tsa Matla a 21-1 bakeng sa squalene Synthesis
Litšenyehelo tsa matla (tse hlahisoang e le limolek'hule tsa ATP) bakeng sa motsoako oa molek'hule e le 'ngoe ea squalene ke eng?
Tharollo. Khethisong ea squalene e tsoang ho acetyl-CoA, ATP e sebelisoa feela sethaleng ha mevalonate e fetoloa ho etsoa isoprene squalene preursor. Ho hlokahala limolek'hule tse tšeletseng tsa isoprene ho haha molek'hule ea squalene, 'me ho hlokahala limolek'hule tse tharo tsa ATP ho hlahisa molek'hule e ngoe le e ngoe e sebetsang. Ka kakaretso, limolek'hule tse 18 tsa ATP li sebelisitsoe molemong oa molek'hule e le 'ngoe ea squalene.
Litholoana tsa cholesterol 'meleng
Ho li-vertebrates, cholesterol e ngata e entsoe ka har'a sebete. Tse ling tsa k'holeseterole e entsoeng moo e kentsoe ka likarolo tsa hepatocytes, empa e romeloa haholo ho e 'ngoe ea mefuta ea eona e meraro: biliary (bile) cholesterol, bile acids kapa cholesterol esters. Li-acid tse tsoang mme matsoai a bona ke hydrophilic derivatives ea cholesterol, e hlophisitsoeng kahare ho sebete mme e kenya letsoho ho cheleng lipids (bona sa feiga. 17-1). Li-cholesterol thehoa ka hara sebete ka ketso acyl-CoA-cholesterol-acyltransferase (ACAT). Enzyme ena e thusa ho fetisoa ha masala a mafura a acid ho tloha coenzyme A ho sehlopha sa hydroxyl sa cholesterol (sa feiga. 21- 38), e fetolang k'holeseterole hore e be mofuta oa hydrophobic o eketsehileng. Li-esters tsa cholesterol tse likarolong tse sephiring tsa lipoprotein li isoa liseleng tse ling tse sebelisang k'holeseterole kapa li bolokiloe ka har'a sebete.
Sa feiga. 21-38. Synthesis ea litheolelo tsa cholesterol. Etherification e etsa hore cholesterol e be sebopeho sa hydrophobic le ho feta sa ho boloka le ho tsamaisa.
Cholesterol e hlokahala bakeng sa lisele tsohle tsa phoofolo e ntseng e hola bakeng sa kemelo ea litho, 'me litho tse ling (mohlala, litšoelesa tsa adrenal le litšoelesa tsa thobalano) li sebelisa cholesterol e le selelekela sa li-hormone tsa steroid (sena se tla tšohloa ka tlase). Cholesterol hape ke selelekela sa vithamine D (bona Setšoantšo sa 10-20, v. 1).
Cholesterol le lipids tse ling li na le lipoprotein tsa plasma
Li-cholesterol tsa cholesterol le cholesterol, joalo ka li-triacylglycerols le phospholipids, ha li na metsi ka bongata, leha ho le joalo, li tlameha ho tloha linthong tseo li neng li entsoe ka ho tsona liseleng moo li tla bolokoa kapa li jeloe teng. Li tsamaisoa ke mali a mali ka mokhoa oa madi a lipoprotein li-macromolecular complexes tsa protheine tse khethehileng tse tsamaisang (apolipoproteins) ka phospholipids, cholesterol, cholesterol esters le triacylglycerols li teng mehahong ena mefuteng e fapaneng ea motsoako.
Apolipoproteins ("apo "e bua ka protheine e se nang lipid ka boeona) e kopana le lipids ho theha likhechana tse 'maloa tsa likarolo tsa lipoprotein - li-complexes tsa spherical tse nang le hydrophobic lipids bohareng le liketane tsa hydrophilic amino acid holimo (Fig. 21-39, a). Ka metsoako e fapaneng ea lipids le liprotheine, ho thehoa likaroloana tsa methapo e mengata e fapaneng - ho tloha ho li-chylomicrons ho ea ho density lipoprotein e phahameng. Lintho tsena li ka aroloa ke ultracentrifugation (Lethathamo 21-1) mme li bonoe ka ho sebelisa li-microscopy tsa elektrone (Setšoantšo sa 21-39, b). Sekhechana se seng le se seng sa lipoprotein se etsa mosebetsi o itseng, o khetholloang ke sebaka sa motsoako, sebopeho sa lipid le dikahare tsa apolipoprotein. Bonyane li-apolipoprotein tse 10 tse fapaneng li fumanoe plasma ea mali a motho (Tafole 21-2), e fapaneng ka boholo, karabelo ka li-antibodies tse ikhethang, le tšebeliso ea likarolo tse fapaneng lihlopheng tse fapaneng tsa lipoprotein. Litho tsena tsa protheine li sebetsa e le lintho tse supang li-lipoprotein liseleng tse itseng kapa li-enzyme tse sebetsang lipoprotein.
Lethathamo 21-1. Li-lipoprotein tsa plasma ea motho
Sebopeho (karoloana e boima,%)
r = 513,000). Karolo ea LDL e na le konokono ea limolek'hule tse ka bang 1,500 tsa li-cholesterol esters, ho potoloha konopo ho na le khetla ea limolek'hule tse 500 tsa cholesterol, limolek'hule tse 800 tsa phospholipids le molek'hule e le 'ngoe ea apoB-100. b - lihlopha tse 'ne tsa lipoprotein, tse bonoang ka microscope ea elektrone (kamora pontsho ea tse mpe). Clockwise, ho qala ho tloha palo e kaholimo ho leqele: li-chylomicrons - le bophara ba 50 ho isa ho 200 nm, PL O NP - ho tloha ho 28 ho isa ho 70 nm, HDL - ho tloha ho 8 ho isa ho 11 nm, le LDL - ho tloha ho 20 ho isa ho 55 nm. Thepa ea lipoprotein e fanoa ka tafole. 21-2.
Chylomicrons, ho buuwang ka Sek. 17, Tsamaisa li-triacylglycerols tsa lijo ho tloha ka mpeng ho ea liseleng tse ling. Tsena ke lipoprotein tse kholo ka ho fetisisa, li na le letsoalo le tlase haholo ebile li na le li-cosacylglycerols tse phahameng ka ho fetisisa. (Bona sa feiga. 17-2). Li-chylomicrons li hlophisitsoe ho ER ea lisele tse epithelial tse kolokileng mala, ebe li fetela ka har'a sistimi ea lisele mme li kena maling a mali ka mothapo o tlase oa subclavian. Chylomicron apolipoprotein e na le apoB-48 (e ikhethang bakeng sa sehlopha sena sa lipoprotein), apoE le apoC-II (Lethathamo 21-2). AroC-II e kenya lipoprotein lipase ka har'a li-capillaries tsa adipose tishu, pelo, mesifa ea masapo le lactating gland ea mammary, ho netefatsa phallo ea mafura a mahala ho tsena. Kahoo, li-chylomicrons li fetisetsa li-acid tse mafura liseleng, moo li tla jelloa kapa li bolokoe e le mafura (sa feiga. 21-40). Masalela a Chylomicron (a lokollotsoe haholo ho li-triacylglycerols, empa a ntse a e-na le cholesterol, apoE le apoB-48) a tsamaisoa ke mali a mali ho ea isibeteng. Sebeteng, li-receptors li tlama ho apoE tse ka har'a masala a chylomicron ebe li amohela ho amoheloa ha tsona ka endocytosis. Ho li-hepatocytes, masalela ana a lokolla cholesterol eo a nang le eona mme a timetsoa ka lysosomes.
Lethathamo 21-2. Li-apolipoprotein tsa plasma lipoprotein
Mosebetsi (haeba o tsejoa)
E kenya ts'ebetsong L CAT, e sebelisana le transporter ea ABC
E thibela L CAT
O kenya ts'ebetsong L CAT, ho tsamaisoa ha cholesterol / tumello
Li tlama ho receptor ea LDL
Chylomicrons, VLDL, HDL
Chylomicrons, VLDL, HDL
Chylomicrons, VLDL, HDL
Ho qala ho hlakisoa ha VLDL le masala a chylomicron
Ha lijo li na le mafura a mangata ho feta kamoo a ka sebelisoang hona joale e le mafura, a fetoha karolo ea "pracylglycerols" e leng karoloana e nang le li-apolipoprotein tse ikhethang. lipoprotein tse tlase haholo (VLDL). Li-carbohydrate tse ngata ka har'a sebete li ka fetoloa hore e be li-triacylglycerols hape li romelloe ka ntle e le VLDL (feiga. 21-40, a).Ntle le li-triacylglycerols, karoloana ea VLDL e na le palo e itseng ea li-cholesterol le li-cholesterol esters, hammoho le apoB-100, apoC-1, apoC-II, apoC III le apoE (Lethathamo 21-2). Li-lipoprotein tsena li boetse li tsamaisoa ke mali ho tloha ho sebete ho ea ho mesifa le mesifa ea adipose, moo, kamora hore lipoprotein lipase e buuoe ke apo-C II, mafura a mahala a mafura a lokolloa ho li-pracylglycerols tsa karolo ea VLDL. Adipocytes e nka acid e mahala ea mafura, e boetse e e fetola li-triacylglycerols, tse bolokiloeng liseleng tsena ka mokhoa oa lipid inclusions (marotholi), myocyte, ka lehlakoreng le leng, hang-hang oxidize mafura a acid e le hore a hlahise matla. Boholo ba masala a VLDL a tlosoa ho potoloha ke li-hepatocytes. Ho amoheloa ha bona, ho ts'oanang le ho monya ha li-chylomicrons, ho kenelletsoa ke li-receptors mme ho latela boteng ba apoE libakeng tsa masala a VLDL (ka kenyelletso 21-2, kamano e pakeng tsa lefu la apoE le lefu la Alzheimer e hlalositsoe).
Sa feiga. 21-40. Lipoprotein le lipid transport, le - lipids li tsamaisoa ke phallo ea mali ka mokhoa oa lipoprotein, tse kopaneng likarolo tse 'maloa le mesebetsi e fapaneng le sebopeho se fapaneng sa liprotheine le lipids (tab. 21-1, 21-2) mme e tsamaellana le botebo ba likarolo tsena. Li-lipids tsa lijo li kopantsoe le li-chylomicrons, boholo ba li-triacylglycerols tse ho tsona li lokolloa ke lipoprotein lipase ho adipose le mesifa ea mesifa ho li-capillaries. Masala a Chylomicron (a nang le protheine le cholesterol e ngata) a haptjoa ke hepatocytes. Li-lipids tsa kahare le cholesterol e tsoang ho sebete e fuoa li-adipose le mesifa ea mesifa ka sebopeho sa VLDL. Ho lokolloa ha lipids ho VLDL (hammoho le tahlehelo ea li-apolipoprotein tse itseng) butle-butle ho fetola VLDLP ho LDL, e tsamaisang cholesterol ho tishu tse eketsehileng kapa e e busetsang sebete. Sebete se tšoara masala a VLDL, LDL le li-remnant tsa chylomicrons ke li-endocytosis tsa receptor-mediated. K'holeseterole e feteletseng linthong tse ling e fetisetsoa hape ho sebete sebopehong sa LDL. Sebeteng, karolo ea k'holeseterole e fetoha letsoai la bile. b - Lisampole tsa mali tsa mali tse nkiloeng kamora ho bolaoa ke tlala (ka ho le letšehali) le ka mor'a ho ja lijo tse nang le mafura a mangata (ka ho le letona). Li-chylomicrons tse entsoeng ka ho ja lijo tse mafura li etsa hore plasma e tšoane le lebese.
Ka tahlehelo ea li-triacylglycerols, karolo ea VLDL e fetoloa ho ba masala a VLDL, e boetse e bitsoa li-density density lipoproteins (VLDL), ho nts'oa pele ha li-triacylglycerols ho VLDL low density lipoproteins (LDL) (tab. 21-1). Karolo ea LDL, e ruileng haholo ho li-cholesterol le cholesterol esters, hape e na le apoB-100, e fetisetsa cholesterol ho li-tishe tsa exthepatic tse nang le li-receptor tse ikhethang tse amohelang apoB-100 likhetleng tsa bona tsa plasma. Li-receptor tsena li buella ho bokelloa ha li-cholesterol le li-cholesterol (joalo ka ha ho hlalositsoe ka tlase).
Keketso 21-2.Teko tsa Teko tsa Eona li tiisa kholo ea lefu la Alzheimer's
Bophelong ba batho, ho na le mefuta e meraro e tsebahalang (liemahale tse tharo) ea mofuta o kenyelletsang apolipoprotein E. Ho li-paleE tsa paleE, APOEZ allele ke eona e atileng haholo bathong (e ka bang 78%), li-APOE4 le APOE2 li-15 ke 7%, ka ho latellana. Allele ea APOE4 e bonahala haholo bathong ba nang le lefu la Alzheimer's, mme kamano ena e lumella ho bolela esale pele ho hlaha hoa lefu lena ka monyetla o phahameng. Batho ba futsitseng APOE4 ba kotsing e kholo ea ho ba le lefu la morao la Alzheimer's. Batho ba homozygous bakeng sa APOE4 ba na le menyetla e 16 ea ho ba le lefu lena, lilemo tse tloaelehileng tsa ba kulang li ka ba lilemo tse 70. Bakeng sa batho ba fuoang likopi tse peli tsa AROEZ, ho fapana le moo, lilemo tse tloaelehileng tsa lefu la Alzheimer li feta lilemo tse 90.
Mohloli oa limolek'hule oa kamano pakeng tsa lefu la apoE4 le lefu la Alzheimer o ntse o sa tsejoe. Ntle le moo, ho ntse ho sa tsejoe hantle hore na apoE4 e ka ama kholo ea likhoele tsa amyloid, tseo ka ho hlakileng e leng sesosa sa lefu la Alzheimer (bona sa feiga. 4-31, v. 1). Maikutlo a shebana le karolo ea khoneha ea apoE ho tsitsitseng sebopeho sa cytoskeleton of neurons. Liprotheine tsa apoE2 le apoEZ li hokahana le liprotheine tse 'maloa tse amanang le li-microtubules tsa neuron, ha apoE4 e sa tlame. Sena se ka potlakisa lefu la li-neuron. Ho sa tsotelehe mochine ona ho ka ba teng, litlhatlhobo tsena li fana ka tšepo ea ho holisa kutloisiso ea rona ea ts'ebetso ea tlhaho ea li-apolipoprotein.
Mofuta oa bone oa lipoprotein - phahameng haholo methapo lipoprotein (HDL), karoloana ena e thehoa ka har'a sebete le ka mpeng e nyane ka sebopeho sa likaroloana tse nyane tse nang le protheine e ngata e nang le cholesterol e nyane hape e se na li-cholesterol esters tse ngata (sa feiga. 21-40). Karolo ea HDL e na le mooA-I, apoC-I, apoC-II le li-apolipoprotein tse ling (Lethathamo 21-2), hammoho le lecithin-cholesterol-acyltransferase (LC AT), e thusang ho thehwa ha li-cholesterol esters tse tsoang lecithin (phosphatidylcholine) le cholesterol (sa feiga. 21-41). L CAT e holim 'a likaroloana tse nchafalitsoeng tsa HDL e fetolela chloromicron cholesterol le phosphatidylcholine le masala a VLDL hore e be li-cholesterol esters, tse qalang ho theha senama, li fetola likaroloana tsa HDL tse sa tsoa etsoa hore e be likaroloana tsa HDL tse holang. Lipoprotein ena e nang le k'holeseterole e ngata e khutlisetsoa sebeteng, moo k'holeseterole e "ntšoa", k'holeseterole ena e fetoloa letsoai la bile.
Sa feiga. 21-41. Karabelo e ts'oaroa ke lecithin-cholesterol-acyltransferase (L CAT). Enzyme ena e teng ka holim 'a likaroloana tsa HDL mme e entsoe keapoA-1 (karolo ea karolo ea HDL). Li-esters tsa cholesterol li bokellana kahare ho likaroloana tse nchafalitsoeng tsa HDL, li li fetohe HDL e holileng tsebong.
HDL e ka kenngoa ka har'a sebete ka li-receptor-mediated endocytosis, empa bonyane li-cholesterol tse ling tsa HDL li isoa liseleng tse ling ka methati e meng. Likarolo tsa HDL li ka tlama liprotheine tsa SR - BI receptor ho membrane ea plasma ea lisele tsa sebete le ho lithane tsa steroidogenic joalo ka litšoelesa tsa adrenal. Li-receptor tsena ha li kopanye le endocytosis, empa phetisetso ea cholesterol le karolo e 'ngoe ea karoloana ea HDL ka seleng. Sekotoana sa "depleated" HDL se kenella maling hape, moo se kenyeletsang likarolo tse ncha tsa lipids tse tsoang ho li-chylomicrons le masala a VLDL. HDL eona eo e boetse e khona ho hapa cholesterol e bolokiloeng liseleng tse eketsehileng ebe e e fetisetsa ho sebete ka ho khutlisa k'holeseterole ea motlakase (Sa feiga 21-40). Ho e 'ngoe ea lintho tse fapaneng tse tsamaeang le lipapatso, tšebelisano' moho le HDL e amohelang lisele tse nang le k'holeseterole e qala ho kenyelletsa cholesterol e tsoang seleng ka har'a likarolo tsa HDL, ebe e fetisetsa k'holeseterole e khutletse sebeteng. Phetohong e 'ngoe e fapaneng ea ho fetisa seleng e ruileng ea cholesterol, kamora ho hlaka ha HDL, apoA-I e buisana le seporokerama se sebetsang, protheine ea ABC. ApoA-I ('me mohlomong HDL) e kenella ka endocytosis, e ntan'o khutlisoa hape, e imetsoe ke cholesterol, e isitsoeng ka har'a sebete.
Protein ABC1 ke karolo ea lelapa le leholo la bakuli ba lithethefatsi tse ngata, ka linako tse ling likoloi tsena li bitsoa bahahlauli ba ABC, hobane kaofela li na le lik'hasete tsa motlakase tsa ATP (ATP - li-Cassette tse tlamang), li na le libaka tse peli tsa transmembrane tse nang le li-helmete tsa transmembrane tse tšeletseng (bona khao. . 11, v. 1). Liprotheine tsena ka mafolofolo li fetisetsa li-ion tse ngata, li-amino acid, livithamini, lihormone tsa acid le letsoai la bile ka li-membrane tsa plasma. Moemeli e mong oa lelapa lena la bakuli ke protheine ea CFTR, eo, ka cystic fibrosis, e senyehileng (bona eketsa. 11-3, v. 1).
Li-esters tsa cholesterol li kena ka seleng ka li-endocytosis tse receptor-mediated
Karolo e 'ngoe le e' ngoe ea LDL e maling e na le apoB-100, e amoheloang ke liprotheine tse khethehileng tsa receptor -Li-receptors tsa LDL ka membrane ea lisele tse hlokang ho tšoara cholesterol. Ho tlangoa ha LDL ho receptor ea LDL ho qala endocytosis, ka lebaka leo LDL le receptor ea eona li kenang ka seleng kahare ho endosome (sa feiga. 21-42). Qetellong, endosome e kopana le lysosome, e nang le li-enzyme tse emisang hydrolyze cholesterol esters, e lokolle cholesterol le mafura acid ho cytosol. ApoB-100 e tsoang LDL e boetse e putlama ho theha li-amino acid tse bolokiloeng ka har'a cytosol, empa receptor ea LDL e qoba ho nyenyefatsa mme e khutlela mobung oa sele ho nka karolo hape ho ts'oaroeng ha LDL. ApoB-100 e teng hape ho VLDL, empa setsi sa eona sa "receptor-binding" ha se khone ho hokahanya receptor ea LDL; ho fetoloa ha VLDLP ho LDL ho etsa hore sebaka se kopanyang receptor ho kenaB-100 se fihlellehe. Tsela ena ea ho tsamaisa k'holeseterole ea mali le endocytosis e tsamaeang le li-receptor-mediated endocytosis ho li-tishu tse ikemiselitseng e ithutile ke Michael Brown le Joseph Goldstein.
Michael Brown le Joseph Goldstein
Sa feiga. 21-42. Ho ts'oaroa ha cholesterol ke endocytosis e amohelang methapo.
Cholesterol, e kenang ka har'a lisele ka tsela ena, e ka kenngoa ka har'a li-membrane kapa ea netefatsoa hape ke ACAT (sa feiga. 21-38) bakeng sa polokelo ea cytosol kahare ho marotholi a lipid. Ha ho na le cholesterol e lekaneng e fumanehang karolong ea mali ea LDL, ho bokellana ha cholesterol e ngata e kenelletseng ho thijoa ka ho fokotsa sekhahla sa tlhahiso ea sona.
Receptor ea LDL e boetse e tlama ho apoE mme e bapala karolo ea bohlokoa ho fumaneng li-chylomicrons le masala a VLDL ke sebete. Leha ho le joalo, haeba li-receptor tsa LDL li sa fumanehe (joalo ka mohlala, mohateng oa panya o nang le gene ea li-receptor ea LDL e sa fumaneheng), masalla a VLDL le chylomicrons a ntse a anngoe ke sebete, le ha LDL e sa amoheloe. Sena se supa boteng ba sistimi e thusang ea polokelo ea li-receptor-mediated endocytosis ea VLDL le masala a chylomicron. E 'ngoe ea li-receptor tsa pokello ke protheine e amanang le LRP (lipoprotein receptor - protein) e amanang le lipoprotein receptors, e tlamahanang leEEE le li-ligand tse ling tse' maloa.
Maemo a 'maloa a molao oa k'holeseterole ea biosynthesis
Cholesterol synthesis ke ts'ebetso e rarahaneng ebile e theko e mafolofolo, ka hona ho hlakile hore 'mele o na le molemo oa ho ba le mochine oa ho laola cholesterol biosynthesis, e phetang palo ea eona ho kenyelletsa se tlang ka lijo. Ho liphoofolo tse anyesang, tlhahiso ea k'holeseterole e laoloa ke khatello ea maikutlo
cholesterol le lihormone glucagon le insulin. Mohato oa phetoho ea HMG - CoA ho mevalonate (sa feiga. 21-34) e fokotsa lebelo tseleng ea metabolic ea sebopeho sa cholesterol (ntlha ea mantlha ea taolo). Karabelo ena e thatafatsoa ke HMG - CoA reductase. Tekanyetso ha e sebetsana le liphetoho maemong a k'holeseterole e tsamaisoa ke sistimi e khahlisang ea ho ngola ea mofuta oa HMG - COA reductase. Mofuta ona, hammoho le li-enzyme tse ling tse fetang 20 tse kenyellelitseng ho kenella le ho kopana ha mafura a k'holeseterole le mafura a seng mafura, e laoloa ke lelapa le lenyenyane la liproteine tse bitsoang liprotheine tse sebetsanang le karolo ea tsamaiso ea liprotheine tsa serol) . Kamora ho kopana, liprotheine tsena li hlahisoa ho endoplasmic reticulum. Motsamaisi oa SREBP oa soluble feela ea qhibilihang o sebetsa e le sesebelisoa sa mongolo o sebelisang mekhoa e hlalositsoeng ho Ch. 28 (v. 3). Leha ho le joalo, sebaka sena sa marang-rang ha se na monyetla oa ho kenella tšebetsong ea mofuta oa hau ha feela e lula molek'hule ea SREBP. Bakeng sa ho kenya ts'ebetso ea transense ea mofuta oa HMG - CoA reductase le mefuta e meng, sethala se sebetsang se hatisitsoeng se arohantsoe le SREBP ka protevage ea protein. Ha cholesterol e phahame, liprotheine tsa SREBP ha li sebetse, li behiloe ho ER mohahong o nang le protheine e 'ngoe e bitsoang SCAP (SREBP - protavage activating protein) (sa feiga. 21-43). Ke SCAP e kopanyang cholesterol le li-sterol tse ling tse 'maloa, li sebetsa joaloka sensor ea sterol. Ha boemo ba sterol bo phahame, motsoako oa SCAP - SREBP mohlomong o sebelisana le protheine e 'ngoe, e bolokang rarahaneng eohle ho ER. Ha boemo ba li-sterols ka seleng bo theoha, phetoho ea boits'oaro ho SCAP e lebisa tahlehelong ea ts'ebetso ea ho boloka, 'me sekepe sa SCAP - SREBP se tloha kahare ho li-vesicles ho ea Golgi. Khemong ea Golgi, liprotheine tsa SREBP li khokhothetsoe habeli ke liprotheine tse fapaneng tse peli, cleavage ea bobeli e lokolla domain name ea "amino-terminal" ho cytosol. Sebaka sena sa marang-rang se ea bokong ebe se kenya letsoho ho hatisoa ha mefuta ea sepheo. Sebaka sa protheine ea Amino-terminal SREBP se na halofo ea bophelo 'me se silafatsoa ka potlako ke li-proteinasomes (bona sa feiga. 27-48, t. 3). Ha boemo ba sterol bo nyoloha ka ho lekana, tokollo ea protheine ea SR EBP e nang le amino terminus e boetse e koetsoe, 'me tšilafalo ea protheine ea libaka tse teng e ntse e lebisa ho koaleheng kapele ho mefuta ea sepheo.
Sa feiga. 21-43. Ts'ebetso ea SR EBP Liprotheine tsa SREB P tse sebetsanang le ntho e laoloang ke sterol (mmala o motala), hang kamora hore li hlahisoe, li hlahisoa ho ER, li theha mofuta o nang le S CAP (mmala o mofubelu). (N le C li supa pheletso ea li-protein le li-carboxyl.) Naheng e tlamelletsoeng ke S-B, liprotheine tsa SRE BP ha li sebetse. Ha boemo ba sterol bo fokotseha, motsoako oa SR EBP-S CAP o fallela sebakeng sa Golgi, mme liprotheine tsa SR EBP li hlakisoa ka tatellano ke liprotheine tse peli tse fapaneng. Sebaka sa protheine ea amino acid e lokolotsoeng ea SR EBP se fetela molek'huleng, moo se hlahisang ho hatisoa ha liphatsa tsa lefutso tsa sterol.
Cholesterol synthesis e boetse e laoloa ke mekhoa e meng e mengata (feiga 21-44). Taolo ea Hormonal e kopantsoe le phetoho e kopaneng ea phetisetso ea NM G-CoA. Enzyme ena e teng ka liforomo tsa phosphorylated (tse sa sebetseng) le tsa dephosphorylated (tse sebetsang). Glucagon e hlohlelletsa phosphorylation (inactivation) ea enzyme, mme insulin e phahamisa dephosphorylation, e kenya ts'ebetso ea enzyme hape e khahla sebopeho sa k'holeseterole. Ho tsepamisa mohopolo ho hoholo ha cholesterol e sebetsang ASAT, e eketsang esterification ea cholesterol bakeng sa ho beoa. Kamora nako, lisele tse ngata tsa cholesterol ea cellular li thibela phetiso ea mofuta oa gene e kenyang setsi sa LDL, e fokotsa tlhahiso ea receptor ena, ka hona, ho bokelloa hoa k'holeseterole maling.
Sa feiga. 21-44. Taolo ea maemo a cholesterol e fana ka teka-tekano lipakeng tsa motsoako le ho monya k'holeseterole lijong. Glucagon e thusa phosphorylation (inactivation) ea NM G -CoA reductase, insulin e khothalletsa dephosphorylation (activation). X - li-metabolites tse sa tsejoeng tsa cholesterol tse khothalletsang protheine ea NM G -CoA reductase.
Cholesterol e sa laoloang e ka lebisa ho mafu a tebileng ho batho. Ha kakaretso ea k'holeseterole e kopaneng le cholesterol e fumanoeng lijong e feta tekanyo e hlokahalang bakeng sa kopano ea membrane, motsoako oa motsoako oa bile le li-steroid, ho bokellana ha cholesterol methapong ea mali (atherosranceotic plaque) ho ka hlaha, ho lebisa ho blockage ea bona (atherossteosis). Linaheng tse tsoetseng pele moruong, ho nyekeloa ke pelo ka lebaka la litšitiso tsa methapo ea methapo ea kutlo e leng sona sesosa se seholo sa lefu. Nts'etsopele ea atherosulinosis e amahanngoa le cholesterol e ngata ea mali mme haholo-holo ka cholesterol e phahameng e lumelletsoeng ke karolo ea LDL; litekanyetso tse phahameng tsa mali HDL, ka lehlakoreng le leng, li ama maemo a methapo ea mali.
Ka lefutso la lefutso (lefutso la liphatsa tsa lefutso), boemo ba cholesterol ea mali bo phahame haholo - atherosulinosis e matla e hlaha ho batho bana ba seng ba le bongoaneng. Ka lebaka la receptor e nang le phoso ea LDL, ho fumanoa ho sa lekanyetsoang ha li-receptor-mediated receptor-mediated receptor-mediated Ka lebaka leo, k'holeseterole ha e tlosoe maling, e ea bokellana ebile e kenya letsoho ho theheng maphephe a atherosselotic. Tsela eo k'holeseterole e tsoelang pele e ntseng e tsoela pele, le ha e le k'holeseterole e ngata maling, hobane cholesterol e tsoang kantle ho lisele e ke ke ea kena seleng ho laola synthesis ea intracellular (sa feiga. 21-44).Bakeng sa kalafo ea bakuli ba nang le lefutso la lefutso le mafu a mang a amanang le serum cholesterol e phahameng, ho sebelisoa lihlopha tsa "statin". Tse ling tsa tsona li fumanoa mehloling ea tlhaho, ha tse ling li entsoe ka indasteri ea litlama. Statins e tšoana le mevalonate (eketsa 21-3) mme ke li-inhibitors tsa NMS-CoA reductase.
Sehlomathiso 21-3. MOEKETSI. Litla-morao tsa lipid le ho thehoa ha li-statins
Lefu la pelo (Coronary pelo lefu la pelo) ke sesosa se ka sehloohong sa lefu le bolaeang linaheng tse tsoetseng pele. Ho koaloa ha methapo ea methapo ea kutlo e tsamaisang mali ho ea pelong ho etsahala ka lebaka la ho thehoa ha mafura a mangata a bitsoang li-atherosselotic plaques; libaka tsena li na le cholesterol, liprotheine tsa fibrillar, calcium, li-cell sheet le likarolo tsa sele. Lekholong la XX. Ho ne ho e-na le ngangisano e matla mabapi le kamano lipakeng tsa arterial obstruction (atherosulinosis) le cholesterol ea mali. Lipuisano tsena le lipatlisiso tse sebetsang ka mokhoa ona li lebisitse ho thehoeng ha lithethefatsi tse sebetsang tse theolelang cholesterol e tlase.
Ka 1913, N.N. Anichkov, rasaense ea tsebahalang oa Russia ebile e le setsebi lefapheng la liteko tsa tlhahlobo, o ile a phatlalatsa mosebetsi moo a ileng a bontša hore mebutlanyana e feptjoang ka lijo tse nang le cholesterol e ngata e baka tšenyo methapong ea mali e tšoanang le litheolelo tsa atherosmithotic likepeng tsa batho ba tsofetseng. Anichkov o ile a etsa patlisiso ea hae ka mashome a mangata a lilemo mme a phatlalatsa liphetho ho limakasine tse tsebahalang tsa Bophirimela. Ka bomalimabe, data ea hae ha ea ka ea ba motheo oa mohlala bakeng sa nts'etsopele ea atherosulinosis ho batho, hobane ka nako eo hypothesis e ne e le teng hore lefu lena ke phello ea tlhaho ea botsofali ebile ha le khone ho thibeloa. Leha ho le joalo, butle-butle bopaki bo ne bo bokella likamano lipakeng tsa serum cholesterol le nts'etsopele ea atherosulinosis (lipid hypothesis), le bo-1960. bafuputsi ba bang ba boletse ka ho hlaka hore lefu lena le ka phekoloa ka meriana. Leha ho le joalo, maikutlo a fapaneng a bile teng ho fihlela phatlalatso ka 1984 ea liphetho tsa tlhahlobo e batsi ea karolo ea cholesterol e tsamaisoang ke US National Institute of Health (Coronary Primary Prevention Trial). Ho bontšitsoe ho fokotseha ho hoholo ha lipalo khafetsa ha myocardial infarction le lichapo tse nang le ho fokotseha ha cholesterol ea mali. Thutong ena, k'holeseterole, e leng resin e arolelanang anid acid, e sebelisitsoe ho theola cholesterol. Liphetho li hlahisitse ho batla litlhare tse ncha hape tse matla tsa kalafo. Ke tlameha ho re lefats'eng la mahlale, lipelaelo mabapi le bonnete ba "lipid hypothesis" li ile tsa nyamela ka ho phethahala feela ka ho hlaha ha li-statin ho ella bofelong ba bo-1980 - mathoasong a bo-1990.
Statin ea pele e fumanoe ke Akira Endo Sankyo Tokyo. Endo o phatlalalitse mosebetsi oa hae ka 1976, leha a sebetsana le bothata ba metabolism ea cholesterol ka lilemo tse 'maloa. Ka 1971, o khothalelitse hore li-cholesterol synthesis inhibitors le tsona li ka ba teng ho bahlahisi ba li-mushroom ba lithibela-mafu tse ithutoang ka nako eo. Ka lilemo tse 'maloa tsa mosebetsi o boima, o ile a hlahlobisisa litso tse fetang 6,000 tsa li-mushroom tse fapaneng, ho fihlela a ba le litholoana tse ntle. Sesebelisoa se hlahisoang se ne se bitsoa compactin. Ntho ena e sebelisitse cholesterol e tlase ho lintja le litšoene. Lithuto tsena li ile tsa hapa tlhokomelo ea Michael Brown le Joseph Goldstein ba Univesithi ea Texas Southwestern Medical Medical. Brown le Goldstein, hammoho le Endo, ba qalile thuto e kopaneng mme ba netefatsa tlhaiso ea hae. Katleho e kholo ea liteko tsa pele tsa kliniki li kenyelletsa lik'hamphani tsa meriana ho ntlafatseng lithethefatsi tsena tse ncha. Ho Merck, sehlopha se etelletsoeng pele ke Alfred Alberts le Roy Wagelos ba ile ba qala tlhahlobo e ncha ea litso tsa li-mushroom mme, ka lebaka la ho sekaseka kakaretso ea litso tse 18, ba fumana sehlahisoa se seng se sebetsang. Ntho ena e ncha e bitsoa lovastatin. Le ha ho le joalo, ka nako e ts'oanang, ho ne ho lumeloa hohle hore tsamaiso ea litekanyetso tse ngata tsa compactin ho lintja e lebisa ho nts'etsopele ea mofetše le ho batlana le li-statins tse ncha ka 1980s. e emisitsoe. Leha ho le joalo, ka nako eo, melemo ea ho sebelisa li-statins ho phekola bakuli ba nang le hypercholesterolemia ea malapa e ne e se e bonahala. Kamora ho buisana le litsebi tsa machabeng le Tsamaiso ea Lijo le Lithethefatsi (FDA, USA), Merck o ile a qala ho theha lovastatin. Phuputso e batsi lilemong tse mashome a mabeli tse latelang ha e so senole phello ea carcinogenic ea lovastatin le moloko o mocha oa lithethefatsi o ileng oa hlaha kamora eona.
Sa feiga. 1. Statins ke inhibitors ea NM G-CoA reductase. Ho bapisa sebopeho sa mevalonate le lihlahisoa tse 'ne tsa meriana (li-statins) tse thibelang ketso ea NM G -CoA reductase.
Maemo inhibit ketso ea HMG - CoA - reductase, e etsisa sebopeho sa mevalonate, 'me ka tsela eo e thibe ho kopana ha k'holeseterole. Ho bakuli ba nang le hypercholesterolemia e bakoang ke bofokoli ho kopi e le 'ngoe ea mofuta oa LDL receptor, ha ho nka lovastatin, boemo ba cholesterol bo fokotseha ka 30%. Setlhare sena se sebetsa le ho feta ha se kopantsoe le li-resine tse ikhethileng tse koahelang li-acid le ho thibela ho amoheloa ha tsona ka mpeng.
Hajoale, li-statins hangata li sebelisetsoa ho theola cholesterol ea mali. Ha u sebelisa meriana leha e le efe, potso e hlaha ka litlamorao tsa eona tse sa rateheng. Leha ho le joalo, litabeng tsa li-statins, litla-morao tse ngata, ka lehlakoreng le leng, li ntle. Lithethefatsi tsena li ka hlohlelletsa phallo ea mali, li lokisa li-plaque tsa methapo ea methapo (e le hore li se ke tsa qhalana le marako a methapo ea mali mme tsa se ke tsa kena-kenana le phallo ea mali), inhibit plateletation, hape ea fokolisa lits'ebetso tsa ho ruruha maboteng a methapo ea mali. Ho bakuli ba nkang li-statins ka lekhetlo la pele, litlamorao tsena li bonahala le pele maemo a cholesterol a qala ho theoha, mme mohlomong a amana le thibelo ea syntoprenoid synthesis. Ho joalo, ha se litla-morao tsohle tsa li-statins tse molemo. Ho bakuli ba bang (hangata har'a ba nkang li-statins hammoho le lithethefatsi tse ling tse fokotsang cholesterol), bohloko ba mesifa le bofokoli ba mesifa bo ka ba teng, 'me ka linako tse ling bo le ka mokhoa o matla. Litlamorao tse ling tse ngata tsa li-statins le tsona li ngolisitsoe, tseo, ka lehlohonolo, li sa hlaheng. Boholo ba bakuli, ho nka li-statin ho ka thibela nts'etsopele ea lefu la pelo le pelo. Joalo ka litlhare tse ling, li-statin li lokela ho sebelisoa feela joalo ka khothaletso ke ngaka ea hau.
Ka lebaka la lefutso la cholesterol ea lefutso la HDL, maemo a cholesterol a fokola haholo, ka lefu la Tangier, k'holeseterole ha e sa khethoa. Mathata ka bobeli a liphatsa tsa lefutso a bakoa ke liphetoho liprotheine tsa ABC1. Karolo ea cholesterol e se nang HDL e ke ke ea hapa k'holeseterole e tsoang liseleng tse haelloang ke ABC1, 'me lisele tse fokolisitsoeng ke k'holeseterole li tlosoa kapele maling le ho felisoa. Ho se be teng hoa lefu la HDL le lefu la Tangier ka bobeli ha ho na seoelo (malapa a ka tlase ho 100 a nang le lefu la Tangier a tsebahala lefatšeng ka bophara), empa mafu ana a bontša karolo ea protheine ea ABC1 ho laola maemo a plasma a HDL. Kaha maemo a HDL a boemo bo tlaase a tsamaellana le litšenyehelo tse phahameng tsa tšenyo ea methapo ea kutlo, protheine ea ABC1 e ka ba sepheo se sebetsang bakeng sa lithethefatsi tse etselitsoeng ho laola maemo a HDL. ■
Lihormone tsa Steroid li thehoa ka ho petsola lehlakore la k'holeseterole le oxidation ea eona.
Motho o amohela lihormone tsohle tsa hae tsa steroid ho cholesterol (sa feiga. 21-45). Mefuta e 'meli ea lihormone tsa steroid e hlophisitsoe kahare ea adrenal cortex: mineralcorticoids,e laolang ho amoheloa ha li-ion tse hlophisitsoeng (Na +, C l - le HC O 3 -) lipelong, le glucocorticoids, e thusang ho laola gluconeogeneis le ho fokotsa karabelo ea ho fokola. Lihormone tsa thobalano li hlahisoa ka har'a lisele tsa pelehi tsa banna le basali le placenta. Har'a bona progesterone e laolang potoloho ea pelehi ea basali, androgens (mohlala, testosterone) le estrogens (estradiol), e amang kholo e ntlafalitsoeng ea litšoaneleho tsa bobeli tsa thobalano ho banna le basali, ka ho latellana. Lihormone tsa Steroid li na le phello maemong a tlase haholo mme ka hona li entsoe ka bongata bo fokolang. Ha ho bapisoa le letsoai la bile, k'holeseterole e nyane e sebelisoa bakeng sa tlhahiso ea lihormone tsa steroid.
Sa feiga. 21-45. Lihormone tse ling li etsoa ka k'holeseterole. Meetso ea tse ling tsa metsoako ena e bonts'oa ho feiga. 10-19, v. 1.
Motsoako oa lihormone tsa steroid o hloka hore ho tlosoe liathomo tse ngata tsa khabone kapa "kaofela ka" ketane ea lehlakore "ea C-17 D-ring ea cholesterol. Ho tlosoa ka lehlakoreng la methapo ho hlaha mitochondria ea li-tisulingenic tishu. Ts'ebetso ea ho tlosa e na le hydroxylation ea liathomo tse peli tse haufi tsa kh'onate ea lehlakore (C-20 le C-22), 'me ke khokahano ea tlamahano e lipakeng tsa bona (sa feiga. 21-46). Ho thehoa ha li-hormone tse fapaneng ho boetse ho kenyelletsa ho hlahisoa ha liathomo tsa oksijene. Liphetoho tsohle tsa hydroxylation le oxidation nakong ea steroid biosynthesis li susumetsoa ke li-oxidases tse sebetsang (eketsa. 21-1) tse sebelisang Nene D PH, O 2 le mitochondrial cytochrome P-450.
Sa feiga. 21-46. Cleavage ea ketane ea lehlakore lehlakoreng la lihormone tsa steroid. Ts'ebetsong ena ea oxidase e nang le ts'ebetso e tsoakiloeng e kopantseng liathomo tsa khabone tse haufi, cytochrome P-450 e sebetsa joalo ka mokolli oa motlakase. Ho ameha hape tšebetsong ke liprotheine tse tsamaisang motlakase, adrenodoxin le adrenodoxin reductase. Mokhoa ona oa ho arola liketane tsa mahlakoreng o ile oa fumanoa mitochondria ea adrenal cortex, moo tlhahiso e sebetsang ea li-steroid e etsahalang. Pregnenolone ke selelekela sa lihoromo tse ling tsohle tsa li-steroid (sa feiga. 21-45).
Li-intermediates tsa Cholesterol biosynthesis li ameha litseleng tse ling tse ngata tsa metabolic.
Ntle le karolo ea eona e le mokena-lipakeng oa cholesterol biosynthesis, isopentenyl pyrophosphate e sebetsa e le moetapele ea qalang tlatsong ea palo e kholo ea li-biomolecule tse etsang mesebetsi e fapaneng ea bioloji (sa feiga. 21- 47). Tsena li kenyelletsa livithamini A, E le K, lipalesa tsa limela tse kang carotene le chlorophyll phytol ketane, rabara ea tlhaho, oli e mengata ea bohlokoa (mohlala, motheo o monko o monate oa oli ea lemone, eucalyptus, musk), lihormone tsa bana tse sa sebetseng tse tsamaisang metamorphosis, dolichols, tse sebetsa joalo ka lipid-soluble carriers ka sebopeho se rarahaneng sa polysaccharides, ubiquinone le plastoquinone - lijene tse tsamaisang motlakase ka mitochondria le chloroplasts. Limolek'hule tsena kaofela ke lisoprenoid tse sebopeho. Ho fumanoe li-isoprenoid tse fetang 20,000 tsa tlhaho, 'me ho tlalehoa tse ncha tse makholo selemo se seng le se seng.
Sa feiga. 21-47. Setšoantšo se akaretsang sa biosynthesis ea isoprenoids. Meetso ea lihlahisoa tse ngata tse felisitsoeng mona li fanoe khaolong. 10 (v. 1).
Prenylation (khokahano e kopantsoeng ea isoprenoid, bona sa feiga. 27-35) ke mochini o tloaelehileng o sebelisang protheine e bokantle bo kahare ba membrane ea lisele tsa mammalian (bona sa feiga. 11-14). Ho liprotheine tse ling, lipid e tlameletsoeng e emeloa ke sehlopha sa li-farnesyl tse 15, ho tse ling ke sehlopha sa li-geranyl tse 20-khabon. Mefuta ena e 'meli ea lipids e hokahanya li-enzyme tse fapaneng. Ho ka etsahala hore liphetoho tsa prenylation li lebise liprotheine tse fapaneng ho latela li-lipid tse fapaneng ho latela hore na li-lipid li khomaretse eng. Prilination ea protheine ke karolo e 'ngoe ea bohlokoa bakeng sa lintho tse tsoang ho isoprene - barupeluoa ba tsela ea cholesterol metabolism.
Kakaretso ea Karolo ea 21.4 Biosynthesis ea Cholesterol, Steroids le Isoprenoids
■ Cholesterol e thehiloe ho tloha acetyl-CoA ka tatellano e kholo ea karabelo ka lipakeng tse kang β-hydroxy-xy-methylglutaryl-CoA, mevalonate, isoprene dimethylallyl pyrophosphate le isopentenyl pyrophosphate. Kholiso ea likarolo tsa isoprene e fa squalene e seng cyclic, e e potoloha ho theha sisteme e lumelletsoeng ka thapo le mokokotlo oa mahlakore a steroid.
■ Mokhoa oa k'holeseterole e tlas'a taolo ea lihormone, 'me ho feta moo, e thibeloa ke ho eketseha ha likhopolo tsa cholesterol ea intracellular, e etsahalang ka phetoho e kopaneng le taolo ea sengoloa.
■ Li-esters tsa cholesterol le cholesterol li tsamaisoa ke mali e le li-lipoprotein tsa plasma. Sekhechana sa VLDL se fetisetsa k'holeseterole, li-cholesterol esters le li-triacylglycerols ho tloha ho sebete ho ea ho li-tishu tse ling, moo li-triacylglycerols li kholisitsoeng ke lipoprotein lipase mme VLDL e fetotsoe ho LDL. Karolo ea LDL e ruisitsoeng ho cholesterol le cholesterol esters e haptjoa ka mokhoa o sa tobang ke li-receptors ke endocytosis, ha apolipoprotein B-100 ho LDL e amoheloa ke li-receptor tsa plasma membrane. HDL e tlosa cholesterol maling, e e fetisetsa ka har'a sebete. Maemo a nang le phepo e nepahetseng kapa bofokoli ba liphatsa tsa lefutso ho cholesterol metabolism li ka lebisa ho atherosulinosis le myocardial infarction.
■ Lihormone tsa Steroid (glucocorticoids, mineralocorticoids le lihormone tsa thobalano) li thehoa ho tsoa ho cholesterol ka ho fetola ketane ea lehlakoreng le ho hlahisa liathomo tsa oksijene tsamaisong ea steroid ea mehele. Lithako tse ling tse ngata tsa isoprenoid li hlahisoa ho tsoa mevalonate ka li-conduction tsa isopentenyl pyrophosphate le dimethylallyl pyrophosphate hammoho le cholesterol.
■ Prenylation ea liprotheine tse ling o li lebisa libakeng tse tlamang ka membrane ea lisele mme e bohlokoa mesebetsing ea tsona ea tlhaho.
Potso 48. Taolo ea metabolism ea mafura a mangata (β-oxidation and biosynthesis). Synthes of malonyl CoA. Acetyl CoA carboxylase, tsamaiso ea ts'ebetso ea eona. Tsamaiso ea li-acyl Co-a ka har'a membrane e ka hare ea mitochondria.
Ka sehloohong
palo ea phenylalanine e ea chekoa
ka litsela tse 2:
bulela
ka lihlopha tsa marang-rang,
phetoho
ka tyrosine.
Ho fetola
phenylalanine ho tyrosine haholo-holo
ho hlokahala hore o tlose ho fetella
phenylalanine, kaha e tsepamisitse mohopolo haholo
Ho na le chefo ho lisele. Thuto
tyrosine ha e na taba
ho tloha khaello ea amino acid ena
ka har'a lisele ha li etsahale.
Ka sehloohong
phenylalanine metabolism e qala
le hydroxylation ea eona (feiga 9-29), ho
e bakang tyrosine.
Boitšoaro bona bo susumetsa ke itseng
monooxy-nat - phenylalanine hydra (zsilase,
e sebeletsang e le molemi ea kopaneng
tetrahydrobiopterin (N4BP).
Ts'ebetso ea enzyme e boetse e itšetlehile ka
boteng ba Fe2.
Ho
sebete se potlakisa ts'ebetso e kholo
glycogen (bona karolo ea 7). Leha ho le joalo
glycogen ka har'a sebete e felile
Lihora tsa 18-24 tsa ho itima lijo. Mohloli o ka sehloohong
glucose ha metšoarelo e fela
glycogen e fetoha gluconeogeneis,
e qalang ho potlakisa
Sa feiga.
11-29. Liphetoho tse kholo tsa metabolic
matla ha o fetola monya
boemo ba postabsorbent. CT
- 'mele ea ketone, FA - acid e mafura.
4-6 h
kamora lijo tsa ho qetela. Metsetsoana
glycerol e sebelisoa ha ho etsoa tsoekere.
amino acid le lactate. E phahameng
Sekhahla sa synthesis ea glucagon
mafura acid e fokotsehile ka lebaka la
phosphorylation le inactivation
acetyl CoA carboxylase le sekhahla
p-oxidation ea eketseha. Empa,
phepelo e eketsehileng ea mafura ho sebete
asiti tse tsamaisoang
ho tsoa litepeng tsa mafura. Ho thehiloe Acetyl-CoA
ka har'a oxidation ea mafura acid, e sebelisoa
ka har'a sebete bakeng sa motsoako oa 'mele oa ketone.
Ho
lithane tsa adipose ka khatello e ntseng e eketseha
Sekhahla sa glucagon se fokotsoe
TAG le lipolysis lia hlohlona. Ho khothatsa
lipolysis - ts'ebetso ea ts'ebetso
li-TAG lipase tse mahlonoko tsa hormone
adipocytes tlasa ts'usumetso ea glucagon.
Li-acid tse mafura li fetoha tsa bohlokoa
mehloli ea matla ho sebete, mesifa le
lithane tsa adipose.
Kahoo
ka hona, nakong ea postabsorption
ts'oarello ea glucose ea mali e ea lula
boemong ba 80-100 mg / dl, le boemo ba mafura
asiti le 'mele oa ketone oa eketseha.
Tsoekere
lefu la tsoekere ke lefu le hlahang
ka lebaka la ho phethahala ka botlalo kapa mong ka wena
khaello ea insulin.
A.
Mefuta ea kliniki e ka sehloohong ea tsoekere
lefu la tsoekere
Ho latela
Mokhatlo oa Lefatše
lefu la tsoekere la bophelo bo botle
classified ho latela liphapang
lintlha tsa lefutso le tliliniki
mefuta e 'meli ea sehlooho: lefu la tsoekere
Mofuta oa I - o itšetlehileng ka insulin (IDDM), le lefu la tsoekere
Type II - non-insulin e ikemetseng (NIDDM).
Molao oa tsamaiso
synthes ea zhk
synthesis of lcd - acetyl CoA carboxylase.
Enzyme ena e laoloa ke ba 'maloa
mekhoa.
Activation / Ho ikarola
Enzyme subunit e rarahaneng. Ho
sebopeho se sa sebetseng sa acetyl CoA carboxylase
e emela likarolo tse fapaneng,
e 'ngoe le e' ngoe e na le litlatsetso tse 4.
Moetsi oa enzyme ke citrate. Hoa tsosa
motsoako oa li-complexes, ka lebaka leo
moo mosebetsi oa enzyme o eketsehang
. Inhibitor-Palmitoyl-CoA. Oa letsetsa
ho ikhetholla ho rarahaneng le ho fokotseha
ts'ebetso ea enzyme.
Phosphorylation / Dephosphorylation
acetyl CoA carboxylase. Ho
boemo ba postabsorption kapa ka
mosebetsi o boima glucagonized
adrenaline ka adenylate cyclase
sistimi e sebetsoa ke prokinase A le
hlohlelletsa subunit phosphorylation
acetyl CoA carboxylase. Phosphorylated
enzyme ha e sebetse le mofuta oa mafura
acid e ea emisa.
Absorbent
insulin activates phosphatase,
mme carboxylase ea acetyl-CoA e kena
boemo bo fokolitsoeng. Ebe
tlasa ts'usumetso ea citrate e etsahala
polymerization ea baetsi ba enzyme, mme
oa ba mafolofolo. Ntle le ts'ebetso
enzyme, citrate e etsa e 'ngoe
sebetsa ho synthesis ea LCD. Absorbent
nako ea mitochondria ea lisele tsa sebete
bokella citrate, eo ho eona
masalla a acyl a isoa teng
cytosol.
Molao oa tsamaiso
Sekhahla sa litefiso tsa oxidation.
Tsela ea oxidation-metabolic,
e hokahane ka thata le mosebetsi oa CPE le kakaretso
mekhoa ea katlase. Ka hona lebelo la eona
e laoloang ke tlhoko ea sele
matla i.e. ka tekanyo ea ATP / ADP le NADH / NAD, hammoho le sekhahla sa karabelo sa CPE le
tsela e tloaelehileng ea katlase. Lebelo
β-oxidation ho li-tishu e itšetlehile ka ho fumaneha
substrate, i.e.
ka palo ea mafura
asiti tse kenang mitochondria.
Free Fatty Acid Concentration
maling a phahama ka lebaka la ts'ebetso
lipolysis ka har'a lithane tsa adipose nakong ea ho itima lijo
tlasa ts'usumetso ea glucagon le nakong ea 'mele
sebetsa tlasa tšusumetso ea adrenaline. Ho tsena
mafura acid e fetoha
mohloli o ka sehloohong oa matla
bakeng sa mesifa le sebete, ka lebaka la
Li-oxidations li thehiloe ke NADH le acetyl-CoA inhibiting
pyruvate dehydrogenase e rarahaneng.
Phetoho ea ho etsa mofuta oa pyruvate
ho tloha tsoekere ho ea ho acetyl-CoA e fokotseha butle.
Li-metabolites tse bohareng lia bokellana
glycolysis 'me, haholo-holo, tsoekere-6-phosphate.
Glucose-6-phosphate inhibits hexokinase
ka hona e nyahamisang
ts'ebeliso ea tsoekere e ts'ebetsong
glycolysis. Ka hona, e ka sehloohong
tšebeliso ea lcd e le mohloli o ka sehloohong
matla ka har'a mesifa ea mesifa le sebete
e boloka tsoekere ho linama tsa methapo le
lisele tse khubelu tsa mali.
Sekhahla sa id-oxidation hape
ho latela ts'ebetso ea enzyme
carnitine acyltransferases I.
Sebeteng, enzyme ena e thibeloa.
malonyl CoA, ntho e thehiloeng
ka biosynthesis ea lcd. Nakong ea ho monya
glycolysis e kenngoa ka har'a sebete le
sebopeho sa acetyl-CoA ea eketseha
ho tloha pyruvate. Karabelo ea pele
lcd phetoho ea acetyl-CoA ho malonyl-CoA.
Malonyl-CoA e thibela β-oxidation ea lcd,
e ka sebedisoang bakeng sa synthesis
mafura.
Thuto
malonyl-CoA e tsoang ho acetyl-CoA-e laolang
karabelo in biosynthesis lcd. Karabelo ea pele
synthesis lcd phetoho ea acetyl-CoA ho
malonyl CoA. Enzyme ea katamelo
karabelo (acetyl Coa carboxylase),
ke ea sehlopha sa ligase. O na le
e kopantsoeng ka kotloloho biotin. Pele
co2 mohato o kopaneng oa karabelo
tlameletsoe ho biotin ka lebaka la matla
ATP, mohato oa 2 COO- e fetiselitsoe
ho acetyl-CoA ho theha malonyl-CoA.
Ketsahalo ea Acetyl CoA Carboxylase Enzyme
e bonts'a lebelo la tsohle tse latelang
synthes reaction lc
citrate e kenya ts'ebetso ea enzyme ho cytosol
acetyl CoA carboxylase. Malonyl CoA ho
ka lehlakoreng le leng e thibela phetisetso ea holimo
mafura acid ho tloha cytosol ho isa matrix
mitochondria mosebetsi o thibelang
kantle acetyl CoA: carnitine acyltransferase,
ka hona, ho tima oxidation ea holimo
mafura a acid.
Acetyl-CoA Oxaloacetate →
HS-CoA Citrate
HSCOA ATP Citrate → Acetyl-CoA ADP Pi Oxaloacetate
Acetyl-CoA
cytoplasm e sebetsa e le karoloana e qalang
bakeng sa motsoako oa lcd, le oxaloacetate ho
cytosol e fetoha liphetoho ho
sephetho sa seo pyruvate e thehoang ka sona.
Cholesterol biosynthesis
Cholesterol biosynthesis e hlaha ho endoplasmic reticulum. Mohloli oa liathomo tsohle tsa khabone ka molek'huleng ke acetyl-SCoA, e tsoang mona e tsoa ho mitochondria ho citrate, joalo ka ha ho kopantsoe li-acid tse mafura. Cholesterol biosynthesis e ja limolek'hule tse 18 tsa ATP le limolek'hule tse 13 tsa NADPH.
Ho thehoa ha cholesterol ho hlaha ka makhetlo a fetang 30, a ka arotsoang ka mekhahlelo e mengata.
1. Synthesis ea mevalonic acid.
Liphetoho tsa pele tse peli li tsamaisana le karabelo ea ketogeneisis, empa kamora ho qaptjoa ha 3-hydroxy-3-methylglutaryl-ScoA, enzyme ea kena hydroxymethyl-glutaryl-ScoA reductase (HMG-SCOA reductase), e theha mevalonic acid.
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