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• W1552547230 abstract "Human cells maintain lipid homeostasis by regulated cleavage of membranebound transcription factors, so-called sterol-regulatory element-binding proteins (SREBPs). The mature forms of SREBP-1 and -2 are transcriptional activators of lipogenic genes controlling cholesterol, fatty acids, and triglyceride biosynthesis and uptake. As the SREBPs play a central role in the regulation of the lipoprotein metabolism, we supposed that specific sequence variations, which correspond to single-nucleotide polymorphisms in these genes, and certain drugs, that influence the expression of SREBP, may result in alterations in plasma lipoprotein concentrations. A syndrome characterized by hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia and lipodystrophy has been found to be associated with antiretroviral treatment (ART) including protease inhibitors. A marker predicting this syndrome has been identified in the gene encoding the sterolregulatory element-binding protein-1c (SREBP-1c), a regulator of triglycerides, cholesterol, insulin and adipocytes. A possible inhibition of SREBP-1c-dependent genes by the protease inhibitor indinavir and its possible reversal by the lipid-lowering drug simvastatin were studied in cell culture. The effects of indinavir and simvastatin on SREBP-1c-dependent genes were compared with the effects of indinavir and simvastatin on SREBP1c-independent genes. In fact, indinavir inhibited the SREBP-1c-dependent genes encoding the lipoprotein lipase and the fatty acid synthase in a dosedependent manner but not the SREBP-1c-independent gene encoding the low-density lipoprotein receptor. Furthermore, simvastatin antagonized the indinavir-induced SREBP-1c-inhibition. Thus, indinavir inhibits important effector genes of the SREBP-1c pathway, which may explain major antiretroviral treatment-related adverse effects. A single-nucleotide polymorphism (3' 322C/G SNP) identified in the sterolregulatory element-binding protein-1c (SREBP-1c) gene was predictive of highly active antiretroviral therapy-related hyperlipoproteinemia. Increases in cholesterol, triglyceride and insulin were less frequently associated with homozygous SREBP-1c-3' 322G (genotype 22) than with heterozygous/homozygous SREBP-1c-3'322C (genotypes 11/12). Thedifferences in messenger RNA conformation can explain the pharmacogeneticbasis of these findings. The mRNA stability of both homozygous genotypes ofSREBP-1c-3’322C/G was compared in the stably transfected T-REx cell linesusing a real-time quantitative polymerase chain reaction method. The mRNAof the SREBP-1c-3’322C isoform (genotype 11) was shown to have a moreabundance decay rate than 3’322G isoform (genotype 22). Thus, thesequence variation (3’322C/G SNP) in the coding 3’ end of the gene affectsthe secondary structure of the SREBP-1c mRNA, influences its degradationrate and, therefore, causes differences in the regulation of SREBP-1cexpression.In the process of this thesis, three new splice variants of the human SREBP-1gene that shared different combinations of the SREBP-1a and -1c exons atthe 3’ end of mRNA were identified. The splice variant containing exons 17,18a and 18c was designated as SREBP-1d, the splice variant containingexons 17, 18a, 18c and 19c was termed as SREBP-1e, and the splice variantcontaining exons 17, 18c and 20f was named as SREBP-1f. Analysis of tissuedistribution showed that the new splice variants SREBP-1e and -1d wereubiquitously found in various human tissues and tumor-derived cells, whereaswild-type SREBP-1c and SREBP-1f transcripts were relatively tissue-specific.This high abundance led us to the hypothesis that splice variants SREBP-1eand SREBP-1d play a more general role in regulating cellular lipid levels ascompared to other isoforms.This thesis concludes that the sterol-regulatory element-binding protein(SREBP)-1c is crucial in the metabolic side-effects associated with highlyactive antiretroviral therapy using protease inhibitors. Moreover, regulationmechanism mediated by the transcription factor SREBP-1 is a model of acomplex gene regulation system composed of different related levels:promoter regulation of effector genes, differences in mRNA stability and tissuespecific splice variants in different quantities." @default.
• W1552547230 created "2016-06-24" @default.
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• W1552547230 date "2004-01-01" @default.
• W1552547230 modified "2023-09-23" @default.
• W1552547230 title "Cellular and molecular characterization of the sterol-regulatory element-binding protein-1" @default.
• W1552547230 doi "https://doi.org/10.5451/unibas-003191653" @default.
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