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Značaj određivanja markera sinteza i apsorpcije holesterola kod zdravih ispitanika i pacijenata sa ishemijskom bolešću srca

The importance of cholesterol synthesis and absorption markers determination in healthy subjects and patients with ischemic heart disease.

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2018
Disertacija.pdf (2.605Mb)
IzvestajKomisije20674.pdf (192.2Kb)
Authors
Gojković, Tamara
Contributors
Jelić-Ivanović, Zorana
Šobajić, Slađana
Oštrić-Kalimanovska, Dimitra
Zeljković, Aleksandra
Vekić, Jelena
Doctoral thesis (Published version)
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Abstract
Ateroskleroza predstavlja hroničnu, fokalnu bolest intime krvnih sudova. Iako jeveliki broj etioloških faktora uključen u patogenezu i progresiju ateroskleroze,dislipidemija ima ključnu ulogu u razvoju ateroma. Ateroskleroza se nalazi u osnovi većinekardiovaskularnih bolesti (KVB), uključujući i ishemijsku bolest srca (IBS). Statinipredstavljaju hipolipemike izbora u primarnoj i sekundarnoj prevenciji KVB. Pored dejstvana inhibiciju sinteze holesterola, statini ostvaruju i brojne plejotropne efekte. U rutinskojpraksi za postavljanje dijagnoze dislipidemije i praćenje odgovora na terapiju statinimakoriste se osnovni parametri lipidnog statusa. Međutim, za sagledavanje celokupnogmetabolizma holesterola i praćenje njegove homeostaze, neophodno je odrediti efikasnostsinteze i apsorpcije holesterola, njegovu raspodelu između lipoproteinskih čestica, kao iočuvanost funkcije reverznog transporta holesterola. Homeostaza holesterola predstavljaravnotežu između sinteze i apsorpcije holesterola. ...Određivanje koncentracija prekursora usintezi holesterola (dezmosterol i latosterol) i fitosterola (kampesterol, stigmasterol i β-sitosterol) kao surogat-markera apsorpcije holesterola, može ukazati na rani razvojdislipidemije i predvideti odgovor na terapiju statinima. Jednim imenom ovi markeri senazivaju neholesterolski steroli (NHS). Relativno niske koncentracije NHS predstavljajuspecifičan problem za njihovu kvantifikaciju. Ovo je dodatni razlog za opsežnu validacijumetoda za određivanje NHS, kao i za utvrđivanjem preanalitičkih i analitičkih faktorauticaja na kvantifikaciju NHS. Kako bi se doprinelo boljem razumevanju metabolizmaholesterola i uticaja terapije statinima na homeostazu holesterola, ciljevi ove studije su bili:uspostavljanje i validacija metode za određivanje NHS; određivanje koncentracija NHSkod zdravih ispitanika (KG) i pacijenata sa IBS; određivanje obrazaca homeostazeholesterola i njihove povezanosti sa osnovnim parametrima lipidnog statusa i raspodelomlipoproteinskih čestica male gustine (LDL) u ispitivanim grupama, i određivanje masenekoncentracije fosfolipaze A2 udružene sa lipoproteinom (Lp-PLA2).U istraživanju je učestvovala 31 zdrava osoba, 32 pacijenta sa IBS na terapijistatinima i 47 pacijenata sa IBS bez terapije hipolipemicima. Koncentracije NHS iprocentualni udeli pojedinačnih masnih kiselina (MK) u odnosu na ukupanmasnokiselinski sastav plazme određivani su metodom gasne hromatografije sa plamenojonizacionomdetekcijom (GC-FID). Relativni udeli pojedinih subklasa lipoproteinaodređeni su gradijent-gel elektroforezom. Masene koncentracije Lp-PLA2 određene suELISA imunohemijskom metodom...

Atherosclerosis is a chronic, focal disease of the blood vessel intima. Even thoughmany etiological factors are involved in the pathogenesis and progression ofatherosclerosis, dyslipidemia has the key role in atheroma development. Atherosclerosis isthe underlying cause of the most cardiovascular diseases (CVD), including coronary arterydisease (CAD). Statins represent a hypolipemics of choice in primary and secondary CADprevention. In addition to the inhibitory effect on cholesterol synthesis, statins also havenumerous pleiotropic effects. Basic lipid parameters are used for diagnosing dyslipidemiaand monitoring the statin therapy response in clinical practice. However, in order toexamine the overall cholesterol metabolism and monitor its homeostasis, it is necessary toexamine the efficiency of cholesterol synthesis and absorption, its distribution betweenlipoprotein particles, and the preservation of the reverse cholesterol transport function.Cholesterol homeostasis represents the bal...ance between cholesterol synthesis andabsorption. Non-cholesterol sterols (NCSs) represent cholesterol synthesis precursors(desmosterol and lathosterol) and cholesterol absorption surrogate markers (phytosterols -campesterol, stigmasterol and β-sitosterol). These markers can indicate early developmentof dyslipidemia and predict response to statin therapy. Relatively low NCSs concentrationsrepresent a specific problem for their quantification. This represents the additional reasonto conduct an extensive method validation for NCSs determination, as well as to resolvepre-analytical and analytical factors of influence. In order to contribute to a betterunderstanding of cholesterol metabolism and the statin effects on cholesterol homeostasis,the objectives of this study were: establishing and validating the method for NHSsdetermination; determination of NHSs concentrations in healthy subjects (CG) and CADpatients; determination of cholesterol homeostasis patterns and their association with basiclipid parameters and distribution of low-density lipoprotein subclasses (LDL) in examinedgroups, and dtermination of lipoprotein-associated phospholipase A2 concentration.The study included 31 healthy controls (CG), 32 statin-treated patients and 47statin-naive CAD patients. The NCSs concentrations and fatty acid (FA) profiles weredetermined by gas chromatography-flame ionization detection (GC-FID). Lipoproteinsubclasses were separated by gradient gel electrophoresis and lipoprotein-associatedphospholipase A2 concentration has been determined by ELISA assay...

Keywords:
dislipidemija / dyslipidemia / neholesterolski steroli / homeostaza holesterola / validacija metode. / non-cholesterol sterols / cholesterol homeostasis / methodvalidation
Source:
Универзитет у Београду, 2018
Publisher:
  • Универзитет у Београду, Фармацеутски факултет
Projects:
  • Interactive role of dyslipidemia, oxidative stress and inflammation in atherosclerosis and other diseases: genetic and biochemical markers (RS-175035)
[ Google Scholar ]
URI
http://eteze.bg.ac.rs/application/showtheses?thesesId=6820
http://nardus.mpn.gov.rs/handle/123456789/11251
https://fedorabg.bg.ac.rs/fedora/get/o:19912/bdef:Content/download
http://vbs.rs/scripts/cobiss?command=DISPLAY&base=70036&RID=2048345698
https://farfar.pharmacy.bg.ac.rs/handle/123456789/3675
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