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The Study of Mechanisms of Hepatotoxic and Hepatoprotective Effects in a Model of Damaged Hepatocytes
Moravcová, Alena ; Lotková, Halka (advisor) ; Kmoníčková, Eva (referee) ; Kanďár, Roman (referee)
Liver damage has a variety of causes. Due to the role of liver in the metabolism of xenobiotics, liver damage is often caused by toxic substances. Despite the variety of causes, the mechanisms of damage may be common. Most often, oxidative stress is induced in the cell or important organelles are directly damaged. This leads to cell death, the initiation of an inflammatory response and the development of fibrosis. A major problem in Western civilization is Non Alcoholic Fatty Liver Disease (NAFLD), in which fat is stored in liver tissue. Steatotic hepatocytes may be more sensitive to damage compared to non-fatty ones. The study of hepatotoxicity and possible hepatoprotection requires suitable models for in vitro experiments. The first part of this work is therefore dedicated to the introduction of a model background using hepatocytes isolated from rat liver. First, we introduced a method of culturing hepatocytes in a sandwich and evaluated its benefit over cultivation in a monolayer, even for experiments lasting 48 hours, which are frequently used in our laboratory. Significant differences were recorded from day 4 of culture, when the sandwich model provides better preservation of morphological and functional parameters of hepatocytes. However, for our purposes of studying the mechanisms of...
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Effect of GLP-1 on liver metabolism in experiment
Fontana, Josef ; Anděl, Michal (advisor) ; Lotková, Halka (referee) ; Vištejnová, Lucie (referee)
1 Summary GLP-1 (glucagon-like peptide-1) is a peptide hormone belonging to the group of incretins that is secreted postprandially from enteroendocrine L-cells. Number of studies described its effects to lower blood glucose level and to positively affect the B-cells of the islets of Langerhans (reducing apoptosis and accelerating their differentiation). The relationship of GLP-1 to liver cells is intensively studied. Studies described that GLP-1, its analogues or inhibition of dipeptidyl peptidase-4 have a wide range of effects in the liver. For our work was crucial that effects on lipid and saccharide metabolism in the liver were described, as well as modulation of processes related to endoplasmic reticulum stress, oxidative stress and formation of inflammatory mediators. These processes play an essential role in both: pathological conditions (eg. liver diseases NAFLD/NASH) and in the process of liver regeneration. Works describing the potential effect of incretin-based therapies in the treatment of liver diseases (especially NAFLD and NASH) were available prior to the start of our work. In contrast, results of studies on the effect of GLP-1 on the process of liver regeneration and proliferation and apoptosis of hepatocytes were very limited in the literature. The aim of our work was to elucidate the...
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Effects of n-3 polyunsaturated fatty acids on development of non-alcoholic fatty liver disease in experiment, prevalence in patients with type 2 diabetes mellitus and metabolic syndrome, non-invasive diagnostics
Dvořák, Karel ; Brůha, Radan (advisor) ; Ehrmann, Jiří (referee) ; Lotková, Halka (referee)
This thesis focuses on the effects of n-3 polyunsaturated fatty acids (n-3 PUFA) on development of non-alcoholic fatty liver disease (NAFLD) in experiment, on prevalence of this condition in patients with type 2 diabetes mellitus and metabolic syndrome and also on non-invasive diagnostics. The aim was to study the effect of n-3 PUFA on NAFLD development in an experimental model and based on analysis of a group of patients with type 2 diabetes and metabolic syndrome to assess the prevalence of this condition. Lastly we aimed to evaluate non-invasive diagnostic methods of liver fibrosis and NASH. We demonstrated beneficial effects of n-3 PUFA administration on NAFLD development in a C57/Bl6 mice high fat methionin-cholin defficient dietary model of NAFLD. n-3 PUFA administration led to biochemical improvement, decrease of lipid accumulation in the liver as well as improvement of histology. These effects are determined by complex modulation of lipid metabolism, mainly due to decrease in availability of fatty acids for triglyceride synthesis in the liver, changes of adipokine levels and amelioration of proinflammatory status in the liver. In a group of type 2 diabetics we found NAFLD prevalence of almost 80%, 14% of these patients had also signs of liver fibrosis or cirrhosis. Non-invasive methods...
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Effects of n-3 polyunsaturated fatty acids on development of non-alcoholic fatty liver disease in experiment, prevalence in patients with type 2 diabetes mellitus and metabolic syndrome, non-invasive diagnostics
Dvořák, Karel ; Brůha, Radan (advisor) ; Ehrmann, Jiří (referee) ; Lotková, Halka (referee)
This thesis focuses on the effects of n-3 polyunsaturated fatty acids (n-3 PUFA) on development of non-alcoholic fatty liver disease (NAFLD) in experiment, on prevalence of this condition in patients with type 2 diabetes mellitus and metabolic syndrome and also on non-invasive diagnostics. The aim was to study the effect of n-3 PUFA on NAFLD development in an experimental model and based on analysis of a group of patients with type 2 diabetes and metabolic syndrome to assess the prevalence of this condition. Lastly we aimed to evaluate non-invasive diagnostic methods of liver fibrosis and NASH. We demonstrated beneficial effects of n-3 PUFA administration on NAFLD development in a C57/Bl6 mice high fat methionin-cholin defficient dietary model of NAFLD. n-3 PUFA administration led to biochemical improvement, decrease of lipid accumulation in the liver as well as improvement of histology. These effects are determined by complex modulation of lipid metabolism, mainly due to decrease in availability of fatty acids for triglyceride synthesis in the liver, changes of adipokine levels and amelioration of proinflammatory status in the liver. In a group of type 2 diabetics we found NAFLD prevalence of almost 80%, 14% of these patients had also signs of liver fibrosis or cirrhosis. Non-invasive methods...
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Influence of Cholestatic Liver Injury on the Elimination and Transport of Drugs
Brčáková, Eva ; Štaud, František (advisor) ; Tilšer, Ivan (referee) ; Lotková, Halka (referee)
The liver is a unique organ with a number of vital functions. Pivotal one is its participation on bile formation and secretion, import, detoxification and excretion of endogenous substances and xenobiotics. Bile formation is essential for both absorption of lipids in intestine and excretion of various endogenous compounds and xenobiotics (e.g. bile acids, bilirubin, cholesterol, phospholipids and drugs). This function is markedly impaired during extrahepatic and intrahepatic cholestasis with partial or complete stoppage of bile flow. Consequently, hepatic and further systemic accumulation of toxic biliary constituents, such as bile acids and bilirubin, occurs. In an effort to compensate this situation, spontaneous anti-cholestatic mechanisms are activated, which provide alternative excretory routes for toxic accumulating compounds (e.g. renal elimination of bile acids and xenobiotics into urine). These mechanisms include changes in the expression, localization and function of respective transporters in liver and kidneys. Another mechanism with a significant impact on bile formation and transport of compounds between bile and blood is blood-biliary barrier formed by connection of hepatocytes by "tight-junctions" and "gap-junctions". While "gap-junctions" exchange substances among cells,...
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