|
|
Regulation of VLDL production in the liver
Jirátová, Markéta ; Kovář, Jan (advisor) ; Cahová, Monika (referee)
The aim of this thesis is to summarize current knowledge about VLDL (very low density lipoprotein) assembly. In the first part of this thesis basic characteristics of lipids and lipoproteins are described. Lipids are the most favourable source of energy for animals. Lipoproteins are the macromolecular complexes that transport hydrofobic lipids in plasma. According to their density, they are classified to five groups: chylomicrons, VLDL, IDL, LDL, HDL. Second part of this thesis is focused on the apolipoproteins - structural peptide components of lipoproteins. The characteristics and functions of major apolipoprotein classes are explained with the main focus on apolipoproteins B that have an important role in VLDL assembly. The process of VLDL assembly is described in detail in the third part of the thesis. VLDL assembly consists of two steps. Pre-VLDL and lipid droplet are synthetized independently in the first step, for which apolipoprotein B-100 and microsomal triglyceride transfer protein (MTP) are essential. Second step is the fusion of pre-VLDL with the lipid droplet. ADP-ribosylation factor 1 (ARF1) and phospholipase D (PLD) are the essential components in the second step. Also apolipoprotein E, apolipoprotein A-V and acyl-coenzym A:cholesterol acyl transferasa 2 (ACAT2) are important. VLDL...
|
|
|
Analysis of the involvement of α2 - AMPK in the beneficial effects of n-3 polyunsaturated fatty acids on obesity - associated metabolic derangements
Jeleník, Tomáš ; Rossmeisl, Martin (advisor) ; Cahová, Monika (referee) ; Pácha, Jiří (referee)
It is well established that n-3 polyunsaturated fatty acids with long chain (n-3 LC-PUFA) have beneficial effects on the obesity-induced metabolic disorders in mice. However, in obese humans, the potency of these fatty acids to positively affect obesity and insulin resistance has been shown to be lower. The aim of the studies described in this thesis was to verify various approaches aimed at increasing efficiency of n-3 LC-PUFA and to study the involvement of 2 subunit of AMP-activated protein kinase (2-AMPK) in the mechanisms of action of these compounds. Firstly, various chemical derivatives of DHA were tested in mice. Substance-2, the -ethyl ester of DHA, completely prevented and even partially reversed the development of obesity, fat accumulation, impaired glucose tolerance, dyslipidemia and white adipose tissue inflammation, even though the dose was only 10 % of that normally used in mice for the treatment with n-3 LC-PUFA. Secondly, the combination of n-3 LC-PUFA and a low-dose of anti-diabetic rosiglitazone prevented, in additive manner, development of dyslipidemia and insulin resistance, reduced the accumulation of body fat and adipocyte hypertrophy, while inducing adiponectin in mice fed a high-fat diet. This treatment also reversed impaired glucose tolerance in obese mice. The major part...
|
|
|
The role of gut microbiome in the development of type 2 diabetes
Movsesian, Lilit ; Cahová, Monika (advisor) ; Funda, David (referee)
In recent decades, ample evidence of the impact of intestinal microbiota and metabolome on the development of type 2 diabetes and other metabolic disorders such as obesity has been obtained. This thesis provides an overview of known information about this correlation and aims to highlight the importance of further research to identify prospective treatments. Bacterial taxa and metabolites most associated with the incidence of diabetes, as well as those associated with improved glucose and insulin tolerance, are considered. The thesis also compares similarities, differences and contradictions of the discussed studies. Key words: type 2 diabetes, obesity, microbiome, metabolome
|
|
|
Targeted analysis and metabolism of fatty acids in mice and humans
Oseeva, Marina ; Kuda, Ondřej (advisor) ; Cahová, Monika (referee) ; Vrkoslav, Vladimír (referee)
Widespread sedentary lifestyle and unhealthy eating habits in the last few decades have resulted in a dramatic increase of the number of people affected by obesity, type 2 diabetes, and cardiovascular diseases. The study of these pathological conditions revealed that impaired metabolism often causes these disorders. Lipid metabolism research has contributed significantly to determining mechanisms underlying metabolic disorders. Omega-3 fatty acids are an interesting target for lipidomics studies because they were shown to lower risk of cardiovascular diseases and are hypothesized to regulate lipid metabolism. In this work, I optimized lipid extraction and chemical modification methods for analysis of fatty acids profile of tissue samples and biofluids using comprehensive two-dimensional gas chromatography coupled to mass spectrometry (GCxGC-MS). At first, I evaluated the relative amount of omega-3 fatty acids in red blood cells (Omega-3 index) of people living in Czech Republic in either the capital city (n=476) or the rural region (n=388). For this large-scale project, I extracted phospholipids from red blood cell (RBC) membranes, transesterified them into fatty acid methyl esters (FAMEs), and measured their profile by GCxGC-MS. The mean Omega-3 index was 3.56 mol % and I detected no significant...
|
|
|
Metabolomics in the study of microbiome
Nazmutdinova, Anastasiia ; Kuzma, Marek (advisor) ; Cahová, Monika (referee)
Inflammatory bowel disease is a serious condition with an incomplete etiology and pathogenesis. In this thesis, a mouse model of sodium dextran sulfate-induced inflammation was used to study different changes in the metabolism of germ-free and conventionally raised mice due to the development of the inflammatory process. NMR metabolomics of fecal, urine and serum samples, combined with uni- and multivariate statistical analysis, were used to characterize the changes. It was shown that the metabolic signature differs between germ-free and conventional mice. In germ-free mice, significant amounts of carbohydrates were found in feces. Their levels decreased during inflammation as they were excreted in urine. In contrast to conventional mice, germ-free mice also excreted large amounts of amino acids in feces during the developing inflammation. Disorders of sugar and protein metabolism found in germ-free mice indicate severe malnutrition caused by inflammation. The results show that the presence of a microbiome represents a protective mechanism against significant disruption in the body. A stability study of fecal extracts of healthy conventionally colonized mice confirmed that none of the identified and quantified metabolites showed significant systemic changes in several consecutively collected...
|
|
|
Role of adiponectin and B-type natriuretic peptide in the regulation of adipose tissue lipolysis
Wedellová, Zuzana ; Štich, Vladimír (advisor) ; Kunešová, Marie (referee) ; Cahová, Monika (referee) ; Horáková, Olga (referee)
Obesity is a most common metabolic disorder worldwide. Prevalence of obesity is consistently growing in all continents during last years. Primarily the increase of incidence of obesity in children is alarming. Obesity is linked to elevated risk of type 2 diabetes, hyperlipidemia, cardiovascular diseases, some cancers and disorders of musculoskeletal system. The cost of the treatment of diseases linked to obesity is annually increasing and obesity represents very important part of costs of health system in developed - and recently also developing - countries. This fact shows the necessity of research in the area of preventive and therapeutic procedures. The development of metabolic disturbances linked to obesity is associated with dysfunction of adipose tissue. Its two main features are: 1) altered secretion of specific substance with hormonal or paracrinne charakter (called adipokines) and 2) elevated mobilization of non- esterified fatty acids (NEMK) from adipose tissue and subsequently their increased release into the circulation (1). In our studies we paid attention to the study of lipolysis. The rate of lipolysis is the primary factor that determines the release of NEFA from adipose tissue. We focused to a role of adiponectin and natriuretic peptid type B (BNP) in the regulation of lipolysis in...
|
|
|
Role of immune and adipose cells in the development of adipose tissue inflammation induced by stress associated with obesity
Kračmerová, Jana ; Rossmeislová, Lenka (advisor) ; Cahová, Monika (referee) ; Daňková, Pavlína (referee)
1 SUMMARY Obesity and overfeeding are associated not only with increased circulating levels of nutrients and metabolites, but also with increased risk of the development of additional disorders, such as cardiovascular diseases, cancer or insulin resistance. Plausible link between obesity and its comorbidities is inflammatory state, observed on the whole body level as well as in AT. As possible initiators of this inflammation, hypertrophied adipocytes were suggested. Adipocytes per se secrete a spectrum of heterogeneous molecules including cytokines. Under the stress conditions, adipocytes and subsequently AT resident immune cells switch to pro-inflammatory state and via secretory signaling attract additional immune cells. Furthermore, hypertrophic adipocytes release higher levels of metabolites that may also contribute to pro- inflammatory polarization of immune cells, mainly macrophages. General aim of this thesis was to investigate connection between impaired levels of nutrients and pro-inflammatory statue and activation of immune cells in healthy (obese and lean) subjects. In the Part one of this thesis, we analyzed acute reaction of immune cells in circulation and AT on artificially elevated levels of nutrients, imitating its increased values typical for metabolic syndrome. HFM ingestion led to...
|
|
|
Regulation of lipogenesis in human adipose tissue: Effect of metabolic stress, dietary intervention and aging.
Šrámková, Veronika ; Rossmeislová, Lenka (advisor) ; Cahová, Monika (referee) ; Kuda, Ondřej (referee) ; Tanti, Jean-Francois (referee)
Adipose tissue (AT) is a complex organ specialised in safe storage and release of energy as lipids. The adipose organ is therefore essential for the maintenance of energy homeostasis. The prototypical cells of AT are adipocytes, emerging from the precursors in a process called adipogenesis. Adipogenesis itself is tightly connected with lipogenesis, i.e. with the synthesis of fatty acids and triglycerides. Various stimuli can disturb adipocyte differentiation and lipogenesis and thus contribute to AT dysfunction and development of associated metabolic diseases. This thesis was endoplasmicfocused on the investigation of lipogenesis in the context of reticulum stress (ERS), calorie restriction and aging. In Project A, we showed that exposition of adipocytes to high acute ERS inhibits expression of lipogenic genes and glucose incorporation into lipids. Moreover, chronic exposure of preadipocytes to ERS impaired both, lipogenesis and adipogenesis. On the other hand, chronic low ERS had no apparent effect on lipogenesis in adipocytes. These effects of ERS could therefore contribute to the worsening of AT function seen in obesity. The capacity of AT to store lipids decreases in aging, possibly due to the accumulation of senescence cells or higher ERS. In Project B, we investigated lipogenic capacity of...
|
|
|
Roles of environmental factors and microbiome in type 1 diabetes
Novotná, Kateřina ; Funda, David (advisor) ; Cahová, Monika (referee)
Type 1 diabetes mellitus (T1DM) is an insulin-dependent autoimmune disease. Its onset is characterized by an autoreactive self-destruction of β-cells within pancreatic islets. T1DM is influenced by multiple genetic predispositions, but since the incidence of the disease has increased dramatically in the past decades, especially in developed, western-type countries, the importance of the environmental factors has become obvious. There are various significant environmental influences that need to be addressed in the equation of variables. This bachelor thesis deals with the environmental variables and their mechanisms in T1DM and focuses on several areas of interest. It introduces frequently used spontaneous animal model of T1DM, pathogenetic mechanisms and T-cells in T1DM as well as regulatory immune cells and their mechanisms, in the light of hygiene and another hypothesis. Next it addresses the role of intestinal microbiota, dietary factors, mucosal immunity, their mechanisms and interactions in T1DM and extends to other, less researched, but important environmental variables such as circadian rhythm in connection with circadian gene expression depending on the rhythmicity of light/dark rotation and timing of food intake throughout the day, psychological/oxidative stress, and the effects of...
|
|
|
The analysis of mechanisms associated with beneficial metabolic effects of marine Omega-3 polyunsaturated fatty acids in different lipid forms.
Pavlišová, Jana ; Rossmeisl, Martin (advisor) ; Maletínská, Lenka (referee) ; Cahová, Monika (referee)
Obesity, one of the most serious health problems of the 21st century, often occurs as a result of an imbalance between energy intake and energy expenditure. Dietary lipids play an important role in the development of obesity, partly because they represent the richest source of energy amongst all macronutrients. It is, however, not only the amount of consumed lipids, but also the composition of fatty acids, which strongly influences health effects of a particular diet. Saturated fatty acids (SFA) are generally considered as unhealthy due to their pro-inflammatory and lipotoxic properties, while monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) represent a healthier alternative, as they are more readily oxidized and do not disrupt biochemical properties of cellular membranes. Amongst PUFA, PUFA of n-3 series (Omega-3) represent an utterly unique class of lipids that have been documented to protect against cardiovascular disease and dyslipidemia in men and improve insulin sensitivity and glucose tolerance primarily in animal models of obesity. Some molecular mechanisms of Omega-3 action have been already uncovered, such as the modification of biological membranes composition, activation of various transcription factors and membrane receptors, and their role as precursors for...
|
guest ::
