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Regulation of cholesterol metabolism in hepatocytes
Ziková, Kateřina ; Vlachová, Miluše (advisor) ; Zlatohlávek, Lukáš (referee)
This thesis summarizes current data about cholesterol metabolism and its regulation in the liver. First part describes cholesterol transport among tissues by lipoproteins. Second part of this work deals with description of metabolic pathways of cholesterol conversion - how the cells obtain and metabolise cholesterol. Almost all cells can synthesize cholesterol or take it up from the circulation. The cells dispose of abundant cholesterol by several mechanisms - they convert cholesterol to cholesteryl esters that can be stored in lipid droplets; they turn cholesterol into oxysterols that can escape easier from the cell; or they export cholesterol through ATP-binding cassette (ABC) transporters. Specialized tissues (adrenal, gonads) transform cholesterol to steroid hormones. However, only the liver can remove cholesterol from the body in physiologically significant amount - it secretes cholesterol into the bile either directly or after conversion to bile acids. Third section deals with regulation of cholesterol metabolism in hepatocyte. Three transcription factors - sterol regulatory element binding protein (SREBP), liver X receptor (LXR), and farnesoid X receptor (FXR) - play the main role in regulation. Their activities are determined by concentration of cellular cholesterol or its metabolites -...
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Genetic determination of cholesterolemia regulation
Vlachová, Miluše ; Kovář, Jan (advisor) ; Vrablík, Michal (referee) ; Kazdová, Ludmila (referee)
Most types of hypercholesterolemia are of polygenic origin. Some genes related to hypercholesterolemia are known, although all genes responsible for cholesterolemia regulation have not been characterised yet. To identify these new genes, animal models with spontaneous defects in cholesterol metabolism could be very useful. Moreover, a number of variations and polymorphisms have been found to influence blood cholesterol levels in humans. Some may also affect cholesterolemia responsiveness to dietary fat. The Prague hereditary hypercholesterolemic (PHHC) rat is a unique model of hypercholesterolemia induced by dietary cholesterol alone (without administration of cholic acid or thyrotoxic drugs). It exhibits modestly increased cholesterolemia when fed chow and responds to a diet containing cholesterol with a several-fold increase of cholesterolemia to concentrations comparable to those observed in hypercholesterolemic patients. Hypercholesterolemia in this model is characterised by accumulation of very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) enriched by cholesterol. In an experiment with tyloxapol (an inhibitor of lipoprotein lipase) we found that PHHC rats on a cholesterol diet incorporated twice as much cholesterol into VLDL as Wistar rats, although liver...
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Pathogenesis of hypercholesterolemia in Prague hereditary hypercholesterolemic (PHHC) rat
Rybáková, Kateřina ; Vlachová, Miluše (advisor) ; Poledne, Rudolf (referee)
Hypercholesterolemia represents a major risk factor of cardiovascular disease. A number of experimental models is used for study of hypercholesterolemia pathogenesis and therapy. This thesis concentrates on characterization of one of these models. Prague hereditary hypercholesterolemic (PHHC) rat is such a suitable model for study of hypercholesterolemia. Although the majority of plasma cholesterol is transported by high density lipoprotein in PHHC rat fed standard diet, PHHC rat fed cholesterol diet develops hypercholesterolemia comparable to that of humans. The advantage of this model is that hypercholesterolemia develops without the need for addition of bile acids or other hepatotoxic substances to the diet. The hypercholesterolemia of PHHC rat is caused by slowed down catabolism of cholesterol-rich very low density lipoprotein (VLDL). These cholesterol-rich particles are synthesized in the liver. We found out that PHHC rat fed 1% cholesterol diet accumulates cholesteryl esters (CE) in the liver and also in the VLDL. Acyl-CoA:cholesterol acyltransferase (ACAT) and microsomal triglyceride transfer protein (MTP) may participate in the increased incorporation CE into VLDL. We found out no difference in ACAT and MTP activities in the liver between PHHC rats and control animals. Neither ACAT activity...
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Regulation of cholesterol metabolism in hepatocytes
Ziková, Kateřina ; Vlachová, Miluše (advisor) ; Zlatohlávek, Lukáš (referee)
This thesis summarizes current data about cholesterol metabolism and its regulation in the liver. First part describes cholesterol transport among tissues by lipoproteins. Second part of this work deals with description of metabolic pathways of cholesterol conversion - how the cells obtain and metabolise cholesterol. Almost all cells can synthesize cholesterol or take it up from the circulation. The cells dispose of abundant cholesterol by several mechanisms - they convert cholesterol to cholesteryl esters that can be stored in lipid droplets; they turn cholesterol into oxysterols that can escape easier from the cell; or they export cholesterol through ATP-binding cassette (ABC) transporters. Specialized tissues (adrenal, gonads) transform cholesterol to steroid hormones. However, only the liver can remove cholesterol from the body in physiologically significant amount - it secretes cholesterol into the bile either directly or after conversion to bile acids. Third section deals with regulation of cholesterol metabolism in hepatocyte. Three transcription factors - sterol regulatory element binding protein (SREBP), liver X receptor (LXR), and farnesoid X receptor (FXR) - play the main role in regulation. Their activities are determined by concentration of cellular cholesterol or its metabolites -...
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