Bile acids (BA), long believed to only have lipid-digestive functions, have emerged as novel metabolic modulators. They have important endocrine effects through multiple cytoplasmic as well as nuclear receptors in various organs and tissues. BA affect multiple functions to control energy homeostasis, as well as glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor and the cytoplasmic G protein-coupled BA receptor TGR5 in a variety of tissues. However, BA also are aimed at many other cellular targets in a wide array of organs and cell compartments. Their role in the pathogenesis of diabetes, obesity and other 'diseases of civilization' becomes even more clear. They also interact with the gut microbiome, with important clinical implications, further extending the complexity of their biological functions. Therefore, it is not surprising that BA metabolism is substantially modulated by bariatric surgery, a phenomenon contributing favorably to the therapeutic effects of these surgical procedures. Based on these data, several therapeutic approaches to ameliorate obesity and diabetes have been proposed to affect the cellular targets of BA.

• MeSH
• bariatrická chirurgie MeSH
• diabetes mellitus terapie   MeSH
• energetický metabolismus fyziologie   MeSH
• glukosa metabolismus   MeSH
• homeostáza fyziologie   MeSH
• inkretiny MeSH
• lidé MeSH
• metabolické nemoci MeSH
• metabolismus lipidů fyziologie   MeSH
• metabolismus fyziologie   MeSH
• obezita terapie   MeSH
• receptory cytoplazmatické a nukleární fyziologie   MeSH
• receptory spřažené s G-proteiny fyziologie   MeSH
• štítná žláza fyziologie   MeSH
• střevní mikroflóra fyziologie   MeSH
• zácpa metabolismus   MeSH
• žlučové kyseliny a soli metabolismus   fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

This review summarizes the importance of bile acids (BA) as important regulators of various homeostatic mechanisms with detailed focus on cytochrome P450 (CYP) enzymes. In the first part, synthesis, metabolism and circulation of BA is summarized and BA are reviewed as physiological ligands of nuclear receptors which regulate transcription of genes involved in their metabolism, transport and excretion. Notably, PXR, FXR and VDR are the most important nuclear receptors through which BA regulate transcription of CYP genes involved in the metabolism of both BA and xenobiotics. Therapeutic use of BA and their derivatives is also briefly reviewed. The physiological role of BA interaction with nuclear receptors is basically to decrease production of toxic non-polar BA and increase their metabolic turnover towards polar BA and thus decrease their toxicity. By this, the activity of some drug-metabolizing CYPs is also influenced what could have clinically relevant consequences in cholestatic diseases or during the treatment with BA or their derivatives.

• MeSH
• játra účinky léků   metabolismus   MeSH
• lidé MeSH
• receptory cytoplazmatické a nukleární metabolismus   MeSH
• systém (enzymů) cytochromů P-450 metabolismus   MeSH
• xenobiotika metabolismus   farmakologie   MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Cholesterol 7alpha-hydroxylase (CYP7A1) plays a crucial role in cholesterol metabolism and has been implicated in genetic susceptibility to atherosclerosis. Thus, an understanding of its transcriptional regulation is of considerable importance. We evaluated the effect of a common -203A>C polymorphism in the CYP7A1 promoter region on the activity of CYP7A1, estimated as the ratios of serum 7alpha-hydroxycholest-4-en-3-one (C4) to either total or non-HDL-cholesterol. The study was performed on patients after resection of the distal ileum, leading to upregulation of CYP7A1 activity (n = 65). Healthy volunteers served as the control group (n = 66). Whereas higher CYP7A1 activity was associated with the -203A allele in the patient group (C4/cholesterol ratio, 29.0 vs. 14.8 microg/mmol, P = 0.032; C4/non-HDL-cholesterol ratio, 53.3 vs. 21.3 microg/mmol in -203AA and -203CC, P = 0.017, respectively), no differences were observed in the healthy controls. We conclude that under physiological conditions, the -203A>C polymorphism in the CYP7A1 gene promoter region does not seem to have any clinically relevant effect. However, in patients with severe bile salt malabsorption, this polymorphism markedly affects CYP7A1 activity.

• MeSH
• cholesterol-7-alfa-hydroxylasa genetika   metabolismus   MeSH
• ileum chirurgie   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• polymorfismus genetický MeSH
• promotorové oblasti (genetika) MeSH
• upregulace MeSH
• žlučové kyseliny a soli biosyntéza   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

In clinical part of the study the hypothesis that hypercholesterolemic patients - carriers of -203C variant in cholesterol 7alpha-hydroxylase (CYP7A1) gene respond to 4-week therapy with bile acid sequestrant by more pronounced decrease in cholesterolemia than -203A variant carriers will be tested. The dynamics of changes in concentration of cholesterol, lipoproteins, glucose and factors affecting insulin sensitivity induced by changes in bile acid metabolism after sequestrant administration will be studied in healthy volunteers. It will be also analyzed how the changes in bile acid metabolism affect glucoregulation and thyroid function. In molecular biology part of the project the dual luciferase assay will be used to analyze in detail the role of particular polymorphisms in promoter region and first intron of CYP7A1 gene (polymorphisms being in tight linkage disequilibrium with -203A/C polymorphism) in regulation of cholesterol-7alpha-hydroxylase gene expression.

V klinické části projektu bude testována hypotéza, že hypercholesterolemičtí pacienti - nositelé varianty -203C v genu kódujícím cholesterol-7alfa-hydroxylasu (CYP7A1) odpovídají na 4týdenní léčbu sekvestranty žlučových kyselin podstatně větším poklesem cholesterolémie než nositelé varianty -203A. Dynamika změn koncentrace cholesterolu, lipoproteinů, glukózy a faktorů ovlivňujících inzulínosenzitivitu indukovaných změnami v metabolismu žlučových kyselin po podání sekvestrantu bude studována u zdravých dobrovolníků. Dále bude analyzováno, jak změny v metabolismu žlučových kyselin ovlivní glykoregulaci a funkci štítné žlázy. V molekulárně biologické části projektu bude metodou duálního luciferasového stanovení detailně analyzována úloha polymorfismů v promotorové oblasti a 1. intronu genu kódujícího CYP7A1 v regulaci exprese cholesterol-7alfa-hydroxylasy.

• MeSH
• cholesterol-7-alfa-hydroxylasa MeSH
• cholesterol MeSH
• genetika MeSH
• inzulinová rezistence MeSH
• žlučové kyseliny a soli MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• vnitřní lékařství
• biologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

Pregnane X receptor (PXR) is a member of the nuclear receptor (NR) superfamily of ligand-activated transcription factors and is activated by a huge variety of endobiotics and xenobiotics, including many clinical drugs. PXR plays key roles not only as a xenosensor in the regulation of both major phase I and II drug metabolism and transporters but also as a physiological sensor in the modulation of bile acid and cholesterol metabolism, glucose and lipid metabolism, and bone and endocrine homeostasis. Post-translational modifications such as phosphorylation have been shown to modulate the activity of many NRs, including PXR, and constitute an important mechanism for crosstalk between signaling pathways and regulation of genes involved in both xenobiotic and endobiotic metabolism. In addition, microRNAs have recently been shown to constitute another level of PXR activity regulation. The objective of this review is to comprehensively summarize current understanding of post-transcriptional and post-translational modifications of PXR in regulation of xenobiotic-metabolizing cytochrome P450 (CYP) genes, mainly in hepatic tissue. We also discuss the importance of PXR in crosstalk with cell signaling pathways, which at the level of transcription modify expression of genes associated with some physiological and pathological stages in the organs. Finally, we indicate that these PXR modifications may have important impacts on CYP-mediated biotransformation of some clinically used drugs.

• MeSH
• biotransformace MeSH
• enzymová indukce účinky léků   MeSH
• interakční proteinové domény a motivy MeSH
• játra účinky léků   enzymologie   metabolismus   MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• posttranskripční úpravy RNA * účinky léků   MeSH
• posttranslační úpravy proteinů * účinky léků   MeSH
• steroidní receptory chemie   genetika   metabolismus   MeSH
• systém (enzymů) cytochromů P-450 genetika   metabolismus   MeSH
• xenobiotika metabolismus   farmakokinetika   toxicita   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Significance: As the central metabolic organ, the liver is exposed to a variety of potentially cytotoxic, proinflammatory, profibrotic, and carcinogenic stimuli. To protect the organism from these deleterious effects, the liver has evolved a number of defense systems, which include antioxidant substrates and enzymes, anti-inflammatory tools, enzymatic biotransformation systems, and metabolic pathways. Recent Advances: One of the pivotal systems that evolved during phylogenesis was the heme catabolic pathway. Comprising the important enzymes heme oxygenase and biliverdin reductase, this complex pathway has a number of key functions including enzymatic activities, but also cell signaling, and DNA transcription. It further generates two important bile pigments, biliverdin and bilirubin, as well as the gaseous molecule carbon monoxide. These heme degradation products have potent antioxidant, immunosuppressive, and cytoprotective effects. Recent data suggest that the pathway participates in the regulation of metabolic and hormonal processes implicated in the pathogenesis of hepatic and other diseases. Critical Issues: This review discusses the impact of the heme catabolic pathway on major liver diseases, with particular focus on the involvement of cellular targeting and signaling in the pathogenesis of these conditions. Future Directions: To utilize the biological consequences of the heme catabolic pathway, several unique therapeutic strategies have been developed. Research indicates that pharmaceutical, nutraceutical, and lifestyle modifications positively affect the pathway, delivering potentially long-term clinical benefits. However, further well-designed studies are needed to confirm the clinical benefits of these approaches. Antioxid. Redox Signal. 35, 734-752.

• MeSH
• biliverdin metabolismus   MeSH
• hem * metabolismus   MeSH
• hemová oxygenasa (decyklizující) metabolismus   MeSH
• hemoxygenasa-1 metabolismus   MeSH
• lidé MeSH
• nemoci jater * MeSH
• oxid uhelnatý metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

INTRODUCTION: Genetic mechanisms among many other factors play a crucial role in the development and progression of nonalcoholic fatty liver disease (NAFLD). The farnesoid X-receptor (FXR) regulates the expression of target genes involved in metabolic and energy homeostasis, so it can be assumed that genetic variations within the NR1H4 gene, encoding FXR, can affect the development or progression of associated diseases, including NAFLD. THE AIM: To study the association of SNP rs11110390 NR1H4 gene with the probability of development and course of NAFLD in children. MATERIALS AND METHODS: 76 children aged 9-17 years and overweight were examined. According to controlled attenuated parameter (CAP) measurement (Fibroscan®502touch) children were divided into 2 groups: group 1 consisted of 40 patients with NAFLD, group 2 was composed by 36 patients without hepatic steatosis. According to genetic testing children were divided into 3 subgroups - children with CC-, CT-, TT-genotype SNP rs11110390 NR1H4 gene. RESULTS: The frequency of TT-genotype SNP rs11110390 NR1H4 gene detection in children with NAFLD was 17.5% versus 2.8% in the control group (p NR1H4 gene the liver stiffness (p NR1H4 (p NR1H4 is associated with an increased probability of NAFLD development in children. An increase in the steatosis degree and liver stiffness in combination with increased taurine-conjugated bile acids fractions in the hepatic and gallbladder's bile, shift in cytokine balance due to a decrease in IL-10 level in children with TT-genotype SNP rs11110390 NR1H4 were observed.

• MeSH
• dítě MeSH
• játra metabolismus   MeSH
• lidé MeSH
• nealkoholová steatóza jater * genetika   metabolismus   MeSH
• proteiny vázající RNA metabolismus   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

In mammals, the white adipocyte is a cell type that is specialized for storage of energy (in the form of triacylglycerols) and for energy mobilization (as fatty acids). White adipocyte metabolism confers an essential role to adipose tissue in whole-body homeostasis. Dysfunction in white adipocyte metabolism is a cardinal event in the development of insulin resistance and associated disorders. This Review focuses on our current understanding of lipid and glucose metabolic pathways in the white adipocyte. We survey recent advances in humans on the importance of adipocyte hypertrophy and on the in vivo turnover of adipocytes and stored lipids. At the molecular level, the identification of novel regulators and of the interplay between metabolic pathways explains the fine-tuning between the anabolic and catabolic fates of fatty acids and glucose in different physiological states. We also examine the metabolic alterations involved in the genesis of obesity-associated metabolic disorders, lipodystrophic states, cancers and cancer-associated cachexia. New challenges include defining the heterogeneity of white adipocytes in different anatomical locations throughout the lifespan and investigating the importance of rhythmic processes. Targeting white fat metabolism offers opportunities for improved patient stratification and a wide, yet unexploited, range of therapeutic opportunities.

• MeSH
• bílé tukové buňky metabolismus   MeSH
• homeostáza MeSH
• lidé MeSH
• management nemoci * MeSH
• metabolismus lipidů fyziologie   MeSH
• obezita metabolismus   terapie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

PHHC rats represent a suitable experimental model of polygenic hypercholesterolemia. It has been found that its metabolic defect is not related to alimentary cholesterol absorption and LDL clearance. We have tested possible changes in cholesterol clearance from the liver to bile acids by analysis of the expression of the cholesterol 7alpha-hydroxylase (cyp7A1) gene in PHHC (N = 20) and Wistar (controls) (N = 19) male rats. The animals were fed standard laboratory diet (CD) or control diet containing 5% fat and 2% cholesterol (HCD) for two weeks. SSCP and RT-PCR were used for mutation analysis and study of gene expression, respectively. Although the basal cholesterolemia in PHHC was similar to controls (1.80 +/- 0.48 and 1.52 +/- 0.39 mmol/l, respectively), it rose in rats fed on HCD to 9.81 +/- 1.65 mmol/l in PHHC rats and only to 2.19 +/- 0.41 mmol/l in controls. Similarly to the basal cholesterol concentration, the gene expression of cyp7A1 in the liver of rats on CD was the same in both compared groups on the control diet. In controls on HCD, cyp7A1 gene expression increased almost 4-fold immediately on the first day and achieved up to approximately 20-multiple basal expression in the end of the feeding period. Compared to the controls, after switching to HCD the cyp7A1 gene expression in PHHC rats did not change dramatically. These results suggest that the cyp7A1 gene plays an important role in development of hypercholesterolemia in PHHC rats.

• MeSH
• cholesterol-7-alfa-hydroxylasa genetika   metabolismus   MeSH
• cholesterol krev   MeSH
• dieta MeSH
• krysa rodu rattus MeSH
• lipoproteiny krev   MeSH
• mutantní kmeny potkanů MeSH
• nukleové kyseliny metabolismus   MeSH
• potkani Wistar MeSH
• regulace genové exprese enzymů MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH

Increasing worldwide prevalence of type 2 diabetes mellitus and its accompanying pathologies such as obesity, arterial hypertension and dyslipidemia represents one of the most important challenges of current medicine. Despite intensive efforts, high percentage of patients with type 2 diabetes does not achieve treatment goals and struggle with increasing body weight and poor glucose control. While novel classes of antidiabetic medications such as incretin-based therapies and gliflozins have some favorable characteristics compared to older antidiabetics, the only therapeutic option shown to substantially modify the progression of diabetes or to achieve its remission is bariatric surgery. Its efficacy in the treatment of diabetes is well established, but the exact underlying modes of action are still only partially described. They include restriction of food amount, enhanced passage of chymus into distal part of small intestine with subsequent modification of gastrointestinal hormones and bile acids secretion, neural mechanisms, changes in gut microbiota and many other possible mechanisms underscoring the importance of the gut in the regulation of glucose metabolism. In addition to bariatric surgery, less-invasive endoscopic methods based on the principles of bariatric surgery were introduced and showed promising results. This review highlights the role of the intestine in the regulation of glucose homeostasis focusing on the mechanisms of action of bariatric and especially endoscopic methods of the treatment of diabetes. A better understanding of these mechanisms may lead to less invasive endoscopic treatments of diabetes and obesity that may complement and widen current therapeutic options.

• MeSH
• bariatrická chirurgie metody   trendy   MeSH
• diabetes mellitus 2. typu mikrobiologie   chirurgie   MeSH
• gastrointestinální endoskopie metody   trendy   MeSH
• gastrointestinální hormony terapeutické užití   MeSH
• krevní glukóza metabolismus   MeSH
• lidé MeSH
• obezita metabolismus   patologie   chirurgie   MeSH
• střeva mikrobiologie   fyziologie   chirurgie   MeSH
• střevní mikroflóra fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH