Single nucleotide polymorphisms located in 5' untranslated regions (5'UTRs) can regulate gene expression and have clinical impact. Recognition of functionally significant sequences within 5'UTRs is crucial in next-generation sequencing applications. Furthermore, information about the behavior of 5'UTRs during gene evolution is scarce. Using the example of the ATP-binding cassette transporter A1 (ABCA1) gene (Tangier disease), we describe our algorithm for functionally significant sequence finding. 5'UTR features (upstream start and stop codons, open reading frames (ORFs), GC content, motifs, and secondary structures) were studied using freely available bioinformatics tools in 55 vertebrate orthologous genes obtained from Ensembl and UCSC. The most conserved sequences were suggested as hot spots. Exon and intron enhancers and silencers (sc35, ighg2 cgamma2, ctnt, gh-1, and fibronectin eda exon), transcription factors (TFIIA, TATA, NFAT1, NFAT4, and HOXA13), some of them cancer related, and microRNA (hsa-miR-4474-3p) were localized to these regions. An upstream ORF, overlapping with the main ORF in primates and possibly coding for a small bioactive peptide, was also detected. Moreover, we showed several features of 5'UTRs, such as GC content variation, hairpin structure conservation or 5'UTR segmentation, which are interesting from a phylogenetic point of view and can stimulate further evolutionary oriented research.

• Klíčová slova
• 5′ untranslated region, ABCA1, bioinformatics, gene regulation, single nucleotide polymorphism,
• MeSH
• 5' nepřekládaná oblast genetika   MeSH
• ABCA1 protein chemie   genetika   MeSH
• anotace sekvence MeSH
• fylogeneze MeSH
• introny genetika   MeSH
• konformace nukleové kyseliny MeSH
• konzervovaná sekvence genetika   MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• nukleotidové motivy genetika   MeSH
• obratlovci genetika   MeSH
• otevřené čtecí rámce genetika   MeSH
• savci genetika   MeSH
• sekvence aminokyselin MeSH
• sekvence nukleotidů MeSH
• sestřih RNA genetika   MeSH
• zastoupení bazí genetika   MeSH
• zesilovače transkripce genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• 5' nepřekládaná oblast MeSH
• ABCA1 protein MeSH
• messenger RNA MeSH

Dyslipidemia (high levels of plasma triglycerides and total cholesterol/LDL-cholesterol and low HDL-cholesterol) is considered as one of the major factors in the development of atherosclerosis and subsequent myocardial infarction. The final value of lipid parameters results from joint action of genetic predispositions and lifestyle factors (primarily smoking status, physical activity and in lower extent also diet). It is estimated that genetic factors are responsible for 40-80 % of the variability of plasma lipid values. Currently are as predictors DL analyzed mainly single nucleotide polymorphisms (SNPs). A fundamental shift in knowledge of genetic determination DL bring genome-wide association studies (GWAs). These revealed several dozen major polymorphisms in a DNA sequence related to lipid levels. Rather surprisingly, these variants are usually not substitutions of the amino acids, or causing a premature stop codon, but substitutions outside the genes. GWAS also found a number of variants within the genes whose function in lipid metabolism was completely unknown (e.g. gene for sortilin). Polymorphisms in genes for APOE, SORT1, LDLR (affect levels of total cholesterol and LDL-cholesterol), CETP, APOA1, ABCA-1, GALNT-2 (influence HDL-cholesterol) and finally in genes for APOA5, LPL or TRIB1 (affect the levels of triglycerides) but explains max. 30 % of the variability of plasma lipids. It is supposed, that rare polymorphisms/mutations and genetic factors unrelated directly to alterations in the DNA sequence (DNA methylation, histone modifications, regulatory RNA molecules) are responsible for the remaining proportion of DL determination.Key words: gene - cholesterol - interaction - mutation - polymorphism - triglycerides.

• MeSH
• ABCA1 protein genetika   MeSH
• adaptorové proteiny vezikulární transportní genetika   MeSH
• apolipoprotein A-I genetika   MeSH
• apolipoprotein A-V genetika   MeSH
• apolipoproteiny E MeSH
• ateroskleróza MeSH
• celogenomová asociační studie MeSH
• dyslipidemie krev   genetika   MeSH
• epigeneze genetická genetika   MeSH
• genetická predispozice k nemoci MeSH
• HDL-cholesterol krev   MeSH
• histonový kód genetika   MeSH
• intracelulární signální peptidy a proteiny genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• LDL-cholesterol krev   MeSH
• LDL-receptory genetika   MeSH
• lidé MeSH
• lipidy krev   MeSH
• lipoproteinlipasa genetika   MeSH
• metabolismus lipidů genetika   MeSH
• metylace DNA genetika   MeSH
• N-acetylgalaktosaminyltransferasy genetika   MeSH
• polypeptid-N-acetylgalaktosaminyltransferasa MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   genetika   MeSH
• transportní proteiny pro estery cholesterolu genetika   MeSH
• triglyceridy krev   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABCA1 protein, human MeSH Prohlížeč
• ABCA1 protein MeSH
• adaptorové proteiny vezikulární transportní MeSH
• APOA1 protein, human MeSH Prohlížeč
• APOA5 protein, human MeSH Prohlížeč
• apolipoprotein A-I MeSH
• apolipoprotein A-V MeSH
• apolipoproteiny E MeSH
• CETP protein, human MeSH Prohlížeč
• HDL-cholesterol MeSH
• intracelulární signální peptidy a proteiny MeSH
• LDL-cholesterol MeSH
• LDL-receptory MeSH
• LDLR protein, human MeSH Prohlížeč
• lipidy MeSH
• lipoproteinlipasa MeSH
• LPL protein, human MeSH Prohlížeč
• N-acetylgalaktosaminyltransferasy MeSH
• protein-serin-threoninkinasy MeSH
• sortilin MeSH Prohlížeč
• transportní proteiny pro estery cholesterolu MeSH
• TRIB1 protein, human MeSH Prohlížeč
• triglyceridy MeSH

AIMS: The effects of cholesteryl ester transfer protein (CETP) inhibition on lipids, inflammation, and markers of high-density lipoprotein (HDL) function, following an acute coronary syndrome (ACS), are unknown. METHODS AND RESULTS: The dal-ACUTE study randomized 300 patients (1 : 1) to dalcetrapib 600 mg/day or placebo within 1 week of an ACS. The primary endpoint was per cent change in HDL-cholesterol (HDL-C) after 4 weeks. Secondary endpoints included apolipoprotein levels, markers of HDL function, and inflammation. Dalcetrapib treatment increased HDL-C and apolipoprotein A1 by 33.7 and 11.8%, respectively (both P < 0.001) and total cholesterol efflux by 9.5% (P = 0.003) after 4 weeks, principally via an increase in non-ATP-binding cassette transporter (ABC) A1-mediated efflux, without statistically significant changes in pre-β1-HDL levels. The increase in total efflux with dalcetrapib correlated most strongly with increases in apolipoprotein A1 and HDL-C (r = 0.46 and 0.43, respectively) rather than the increase in pre-β1-HDL (r = 0.32). Baseline and on-treatment ABCA1-mediated efflux correlated most strongly with pre-β1-HDL levels; in contrast, non-ABCA1-mediated efflux correlated better with apolipoprotein A1 and HDL-C levels. CONCLUSIONS: High-density lipoprotein raised through CETP inhibition with dalcetrapib improves cholesterol efflux, principally via a non-ABCA1-mediated pathway. While HDL-C was increased by one-third, apolipoprotein A1 and total efflux were increased only by one-tenth, supporting the concept of dissociation between improvements in HDL function and HDL-C levels, which may be of relevance to ongoing trials and the development of therapeutic interventions targeting HDL.

• Klíčová slova
• Coronary disease, Lipids, Lipoproteins,
• MeSH
• ABCA1 protein metabolismus   MeSH
• akutní koronární syndrom farmakoterapie   MeSH
• amidy MeSH
• anticholesteremika aplikace a dávkování   MeSH
• apolipoproteiny metabolismus   MeSH
• biologické markery metabolismus   MeSH
• C-reaktivní protein metabolismus   MeSH
• dvojitá slepá metoda MeSH
• estery MeSH
• HDL-cholesterol metabolismus   MeSH
• infarkt myokardu farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lipoproteiny metabolismus   MeSH
• metabolismus lipidů účinky léků   MeSH
• nestabilní angina pectoris farmakoterapie   MeSH
• rozvrh dávkování léků MeSH
• sulfhydrylové sloučeniny aplikace a dávkování   MeSH
• transportní proteiny pro estery cholesterolu antagonisté a inhibitory   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• ABCA1 protein, human MeSH Prohlížeč
• ABCA1 protein MeSH
• amidy MeSH
• anticholesteremika MeSH
• apolipoproteiny MeSH
• biologické markery MeSH
• C-reaktivní protein MeSH
• CETP protein, human MeSH Prohlížeč
• dalcetrapib MeSH Prohlížeč
• estery MeSH
• HDL-cholesterol MeSH
• lipoproteiny MeSH
• sulfhydrylové sloučeniny MeSH
• transportní proteiny pro estery cholesterolu MeSH

α-Tocopheryl succinate (α-TOS) is a promising anti-cancer agent due to its selectivity for cancer cells. It is important to understand whether long-term exposure of tumour cells to the agent will render them resistant to the treatment. Exposure of the non-small cell lung carcinoma H1299 cells to escalating doses of α-TOS made them resistant to the agent due to the upregulation of the ABCA1 protein, which caused its efflux. Full susceptibility of the cells to α-TOS was restored by knocking down the ABCA1 protein. Similar resistance including ABCA1 gene upregulation was observed in the A549 lung cancer cells exposed to α-TOS. The resistance of the cells to α-TOS was overcome by its mitochondrially targeted analogue, MitoVES, that is taken up on the basis of the membrane potential, bypassing the enhanced expression of the ABCA1 protein. The in vitro results were replicated in mouse models of tumours derived from parental and resistant H1299 cells. We conclude that long-term exposure of cancer cells to α-TOS causes their resistance to the drug, which can be overcome by its mitochondrially targeted counterpart. This finding should be taken into consideration when planning clinical trials with vitamin E analogues.

• MeSH
• ABC transportéry genetika   fyziologie   MeSH
• ABCA1 protein MeSH
• alfa-tokoferol terapeutické užití   MeSH
• chemorezistence * MeSH
• genový knockdown MeSH
• mitochondrie účinky léků   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory plic farmakoterapie   MeSH
• nemalobuněčný karcinom plic farmakoterapie   MeSH
• protinádorové látky farmakologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportéry MeSH
• ABCA1 protein MeSH
• alfa-tokoferol MeSH
• protinádorové látky MeSH