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Vplyv vybraných endokrinných disruptorov na metabolismus lipidov v pečeňových bunkových modeloch
Konopová, Veronika
Endocrine Disrupting Compounds (EDCs) are exogenous compounds that interfere with the endocrine system and consequently elicit toxic outcomes. One of their possible consequences in the organism is their negative impact on metabolic processes linked with development of metabolic diseases, including liver steatosis. In this research area, it is important to develop suitable in vitro cellular models. In this thesis, we evaluated the possibility of using of cell model of immortalized human hepatocytes, MIHA cell line, for detection of activation of nuclear receptors, PXR, LXRa a PPARa, which might be targeted by some EDC. We studied in particular the induction of expression of target genes of these receptors, CYP3A4, SCD, PDK4, CPTT1A, with the aim to compare the sensitivity of MIHA cells with a commonly used of liver cells, HepaRG cell line. The results showed that although some EDC (or model ligands of nuclear receptors) may induce the expression of target genes of nuclear receptors in MIHA cells, in general, this cell model appears to be less suitable for studying the impact of EDC than HepaRG cell line. The MIHA cell line, though, allows to study the compounds activating PPARa, which is an important regulator of metabolism of fatty acids in the liver tissue.
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Adjusting Wnt signaling, new regulatory mechanisms of the Wnt pathway
Fafílek, Bohumil ; Kořínek, Vladimír (advisor) ; Stopka, Tomáš (referee) ; Machoň, Ondřej (referee)
4 Abstract The Wnt pathway is one of the major signaling cascades contributing to multiple cellular processes during embryogenesis, and adult tissue homeostasis and regeneration. Moreover, aberrant activation of the Wnt signaling pathway is connected with development of neoplasia, notably colorectal cancer. The aim of the thesis was to identify new ways of the Wnt pathway regulation to understand better physiological as well as non-physiological mechanisms of Wnt signaling. The results are summarized in four publications. The first article deals with TROY, a member of tumor necrosis factor receptor family. We identified TROY as a Wnt target gene during our search for Wnt responsive genes in colorectal cancer cell lines. Additionally, we detected expression of Troy in tumors of two mouse models of intestinal cancer. In the healthy gut, Troy is produced in fast cycling intestinal stem cells where negatively regulates the Wnt pathway. The second study focuses on processing and posttranslational modification of murine Wnt1 and Wnt3a. Wnts are glycosylated and double acetylated by lipid adducts and our results revealed that O-linked acylation of serine is required for the subsequent S-palmitoylation of cysteine. Moreover, acylation of Wnts is connected with their signaling activity which is related to Wnt1 and...
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