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The influence of gut microbiome on NAFLD development
Herbstová, Kateřina ; Horáková, Olga (advisor) ; Vodička, Martin (referee)
The composition of the intestinal microbiome (i.e. the set of microorganisms living in the intestines) can significantly contribute to the overall function of the host organism, its state of health and the development of diseases. The aim of this works is to describe the possible connections between the gut microbiome and the development of NAFLD (non-alcoholic fatty liver disease). NAFLD is a disease caused by excessive storage of fat hepatic cells not due to alcohol abuse.
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Metabolic and genetic risks of development of non-alcoholic fatty liver disease in patients after liver transplantation and its impact on patient and graft survival
Míková, Irena ; Trunečka, Pavel (advisor) ; Červinková, Zuzana (referee) ; Brůha, Radan (referee)
Nonalcoholic fatty liver disease (NAFLD) occurs frequently not only in the general population, but also in liver transplant (LT) recipients. The data about prevalence, evolution, causes and significance of steatosis in patients after LT are limited. In a large retrospective study in LT recipients with histological evaluation of steatosis, we found high prevalence of steatosis (56,4 %) and steatohepatitis (10,4 %), the prevalence of steatosis increased after LT. Pretransplant predictors of steatosis included alcoholic cirrhosis and high BMI, whereas increased alkaline phosphatase and mycophenolate mofetil given initially were protective. Posttransplant predictors of steatosis included BMI, serum triglycerides, alcohol consumption and presence of type 2 diabetes mellitus, whereas increased serum creatinine was protective. Presence of significant steatosis/steatohepatitis was not associated with increased grade of fibrosis. There was no difference between the occurrence of steatosis in surviving and lost grafts. Survival of patients with/without significant steatosis was similar with a trend to higher long-term mortality of patients with significant steatosis. In the evaluation of the impact of TM6SF2 rs58542926 and PNPLA3 rs738409 genotypes of the donor and recipient on pathophysiology of steatosis...
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Pharmacological and metabolic influence on liver mitochondrial functions
Sobotka, Ondřej ; Červinková, Zuzana (advisor) ; Kuncová, Jitka (referee) ; Žurmanová, Jitka (referee)
Liver mitochondria play a crucial role in intermediary metabolism and main metabolic pathways. We evaluated the pharmacological effect on liver mitochondria in vitro using two novel anticancer drugs: 3-bromopyruvate and α-tocopheryl succinate. Metabolic influence on liver mitochondria was performed in vivo by high fat and high cholesterol diet. Toxicity of both drugs was evaluated in cell cultures of hepatocytes isolated from rat and mouse liver. The effect of anticancer drugs on liver mitochondrial functions in vitro was studied on suspensions of isolated liver mitochondria, tissue homogenate and permeabilized hepatocytes. Mitochondrial respiration was measured using high-resolution respirometry. 3-bromopyruvate caused morphological and functional damage of primary rat and mouse hepatocytes in cell cultures; this toxic effect was accompanied by an increase of reactive oxygen species production and mitochondrial dysfunction. 3-bromopyruvate decreased the oxygen consumption of mitochondria energized by substrates for complex I and complex II. α-Tocopheryl succinate caused a decrease of succinate-dependent respiration in all experimental models both in coupled and in uncoupled states. The most pronounced effect of α-tocopheryl succinate was apparent in isolated mitochondria and the least pronounced...
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The role of lipids in the pathogenesis of liver diseases.
Šmíd, Václav ; Muchová, Lucie (advisor) ; Rumlová, Michaela (referee) ; Mičuda, Stanislav (referee)
1 Abstract In this thesis I have focused on the role of lipids in the pathogenesis of liver diseases, specifically on cholestasis and non-alcoholic fatty liver disease (NAFLD). The first major aim was to clarify the changes in liver ganglioside metabolism in various types of cholestasis and to elucidate the role of heme oxygenase-1 (HMOX1) and associated oxidative stress. The second objective was to determine the effects of n-3 polyunsaturated fatty acids (n-3 PUFA) administration on NAFLD development in a rodent dietary model of NAFLD and in patients with metabolic syndrome and NAFLD. Our results suggest that increased ganglioside biosynthesis and their re-distribution might represent a general protective mechanism of hepatocytes under cholestatic conditions (both estrogen-induced and obstructive aetiology). These changes are closely related to oxidative stress and might protect hepatocytes against deleterious effect of accumulated bile acids. The lack of HMOX1 activity and subsequent oxidative stress potentiate pathological changes in the liver and resulted in tissue-specific modulation of synthesis and re-distribution of gangliosides (in vivo and in vitro). Contrary to it, HMOX1 activation has an opposite effect and may represent a general hepatoprotective mechanism. We have proven that observed changes...
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Pharmacological and metabolic influence on liver mitochondrial functions
Sobotka, Ondřej ; Červinková, Zuzana (advisor) ; Kuncová, Jitka (referee) ; Žurmanová, Jitka (referee)
Liver mitochondria play a crucial role in intermediary metabolism and main metabolic pathways. We evaluated the pharmacological effect on liver mitochondria in vitro using two novel anticancer drugs: 3-bromopyruvate and α-tocopheryl succinate. Metabolic influence on liver mitochondria was performed in vivo by high fat and high cholesterol diet. Toxicity of both drugs was evaluated in cell cultures of hepatocytes isolated from rat and mouse liver. The effect of anticancer drugs on liver mitochondrial functions in vitro was studied on suspensions of isolated liver mitochondria, tissue homogenate and permeabilized hepatocytes. Mitochondrial respiration was measured using high-resolution respirometry. 3-bromopyruvate caused morphological and functional damage of primary rat and mouse hepatocytes in cell cultures; this toxic effect was accompanied by an increase of reactive oxygen species production and mitochondrial dysfunction. 3-bromopyruvate decreased the oxygen consumption of mitochondria energized by substrates for complex I and complex II. α-Tocopheryl succinate caused a decrease of succinate-dependent respiration in all experimental models both in coupled and in uncoupled states. The most pronounced effect of α-tocopheryl succinate was apparent in isolated mitochondria and the least pronounced...
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