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Interaction between adipocytes and immune cells in pathogenesis of obesity related pro-inflammatory state of adipose tissue
Mališová, Lucia ; Rossmeislová, Lenka (advisor) ; Flachs, Pavel (referee) ; Kazdová, Ludmila (referee)
Obesity is considered to be a worldwide epidemic disease characterized by an accumulation of AT. Increased adiposity can perturb normal metabolic functions and lead to the development of diseases like insulin resistance and other metabolic disorders. A large amount of clinical studies have been shown that changes in inflammatory signaling in adipose tissue cells, increased infiltration of immune cells into AT as well as stress of endoplasmic reticulum belong to the key molecular steps leading to the development of metabolic disturbances associated with this disease. Adverse metabolic effects of AT accumulation can be diminished by calorie restriction resulting in weight loss. In addition, stress of endoplasmic reticulum could be alleviated by chemical chaperones including bile acids. These two approaches for the treatment of obesity or the obesity-associated disturbances were basis for this PhD thesis. In the first part of this work, we studied inflammation status of gluteal in comparison with abdominal AT and differentiation and secretory capacity of adipocytes after weight loss in obese patients. We revealed that inflammatory profile of gluteal AT, estimated by mRNA level of macrophages and cytokines as markers of inflammatory status of the body, did not explain the different clinical impact of...
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The role of cholesterol-7alpha-hydroxylase in cholesterolemia regulation
Procházková, Martina ; Kovář, Jan (advisor) ; Zelenka, Jaroslav (referee)
Cholesterol 7α-hydroxylase (CYP7A1) is an enzyme catalyzing the first step of conversion of cholesterol to bile acids. The enzyme activity is regulated to supply enough bile salts necessary for absorption of fats in the intestine. In some species it contributes to cholesterol elimination from the body when dietary cholesterol intake is high and, in such a way, protects against the development of hypercholesterolemia. CYP7A1 activity can be therapeutically affected by administration of bile acid sequestrants that increase the enzyme activity and thus lower cholesterolemia, and also by administration of bile salts. The enzyme deficiency in humans results in hypercholesterolemia. Several single nucleotide polymorphisms were identified in gene encoding CYP7A1 in humans. They form three large haplotype blocks. The most attention has been paid to the -203A>C polymorphism that has an impact on cholesterol and lipoprotein concentrations, on the response of cholesterolemia to dietary intervention and on the response to hypolipidemic drugs. Key words: Bile acids, cholesterol, cholesterol 7α-hydroxylase, diet, genetics, treatment of hypercholesterolemia
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The role of cholesterol 7alpha-hydroxylase in regulation of cholesterolemia
Cejpková, Monika ; Kovář, Jan (advisor) ; Leníček, Martin (referee)
The aim of the theses is to characterize the mechanism that participate in the regulation of activity of cholesterol 7α-hydroxylase (CYP7A1) - the key enzyme of classical pathway of bile acids synthesis. The function and metabolism of cholesterol and bile acid is described at the beginning. Cholesterol is a substrate for CYP7A1 and bile acids are produced in the reaction catalyzed by the enzyme. The other parth of theses is dedicated to feedback inhibition of CYP7A1 by bile acids and describes particular regulatory pathways involved. The crucial factors for CYP7A1 expression are bile acids response elements (BARE) in the promoter of CYP7A1 gene. Central role is played by farnesoid X receptor activated by bile salts that induces expression of protein called small heterodimer partner (SHP) in the liver. SHP interacts with trancription factors in BARE and inhibits CYP7A1 transcription. In the instestine FXR induces fibroblast growth factor 19 (FGF19) that activates signalling pathways leading to inhibition of CYP7A1 in the liver. The activity of CYP7A1 can be regulated independently of FXR - there is a role for hormones (insulin, glucagon), glucose, activation of proinflammatory cytokines and other nuclear receptors (pregnane X receptor and vitamin D receptor), that participate in protection of the...
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