BACKGROUND: Bile salts of hepatic and microbial origin mediate interorgan cross talk in the gut-liver axis. Here, we assessed whether the newly discovered class of microbial bile salt conjugates (MBSCs) activate the main host bile salt receptors (Takeda G protein-coupled receptor 5 [TGR5] and farnesoid X receptor [FXR]) and enter the human systemic and enterohepatic circulation. METHODS: N-amidates of (chenodeoxy) cholic acid and leucine, tyrosine, and phenylalanine were synthesized. Receptor activation was studied in cell-free and cell-based assays. MBSCs were quantified in mesenteric and portal blood and bile of patients undergoing pancreatic surgery. RESULTS: MBSCs were activating ligands of TGR5 as evidenced by recruitment of Gsα protein, activation of a cAMP-driven reporter, and diminution of lipopolysaccharide-induced cytokine release from macrophages. Intestine-enriched and liver-enriched FXR isoforms were both activated by MBSCs, provided that a bile salt importer was present. The affinity of MBSCs for TGR5 and FXR was not superior to host-derived bile salt conjugates. Individual MBSCs were generally not detected (ie, < 2.5 nmol/L) in human mesenteric or portal blood, but Leu-variant and Phe-variant were readily measurable in bile, where MBSCs comprised up to 213 ppm of biliary bile salts. CONCLUSIONS: MBSCs activate the cell surface receptor TGR5 and the transcription factor FXR and are substrates for intestinal (apical sodium-dependent bile acid transporter) and hepatic (Na+ taurocholate co-transporting protein) transporters. Their entry into the human circulation is, however, nonsubstantial. Given low systemic levels and a surplus of other equipotent bile salt species, the studied MBSCs are unlikely to have an impact on enterohepatic TGR5/FXR signaling in humans. The origin and function of biliary MBSCs remain to be determined.
- MeSH
- játra metabolismus MeSH
- lidé MeSH
- receptory cytoplazmatické a nukleární * metabolismus MeSH
- receptory spřažené s G-proteiny * metabolismus MeSH
- transkripční faktory MeSH
- žluč chemie MeSH
- žlučové kyseliny a soli * farmakologie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The aim of this article is to introduce the topic of newly designed peptides as well as their biological activity. We designed nine encoded peptides composed of six amino acids. All these peptides were synthesized with C-terminal amidation. To investigate the importance of increased hydrophobicity at the amino end of the peptides, all of them were subsequently synthesized with palmitic or lithocholic acid at the N-terminus. Antimicrobial activity was tested on Gram-positive and Gram-negative bacteria and fungi. Cytotoxicity was measured on HepG2 and HEK 293 T cell cultures. Peptides bearing a hydrophobic group exhibited the best antimicrobial activity. Lipopeptides with palmitic or lithocholic acid (PAL or LCA peptides) at the N-terminus and with C-terminal amidation were highly active against Gram-positive bacteria, especially against strains of Staphylococcus aureus and Candida tropicalis. The LCA peptide SHP 1.3 with the sequence LCA-LVKRAG-NH2, had high efficiency on HepG2 human liver hepatocellular carcinoma cells (97%).
- MeSH
- antibakteriální látky * farmakologie MeSH
- gramnegativní bakterie MeSH
- grampozitivní bakterie MeSH
- HEK293 buňky MeSH
- kyselina lithocholová MeSH
- lidé MeSH
- lipopeptidy * farmakologie MeSH
- mikrobiální testy citlivosti MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- biologické markery analýza MeSH
- enzymy analýza MeSH
- gama-glutamyltransferasa analýza MeSH
- jaterní testy MeSH
- kyselina ursodeoxycholová aplikace a dávkování farmakologie MeSH
- lidé MeSH
- metabolický syndrom * diagnóza komplikace terapie MeSH
- nemoci jater * diagnóza etiologie terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
BACKGROUND & AIMS: Severity of portal hypertension is usually quantified by measuring the hepatic venous pressure gradient (HVPG). However, due to its invasiveness, alternative markers are being sought. Bile acids (BA), being synthesized, metabolized, and transported by the liver, seem to have the potential to serve as endogenous markers. The aim of the present study was to determine whether serum BA reflect the severity of portal hypertension. METHODS: We correlated serum concentrations of individual BA with portal pressure (as HVPG) in an exploratory cohort of 21 cirrhotic patients with portal hypertension. The predictive potential of selected candidates was then confirmed in an independent validation cohort (n = 214). Additionally, nine previously published noninvasive markers were added to the stepwise logistic regression model to identify the most relevant ones, which were eventually used to create a prognostic index of portal hypertension. RESULTS: Serum levels of taurochenodeoxycholic acid (TCDCA) significantly correlated with HVPG and showed a high potential to predict clinically significant portal hypertension (HVPG ≥ 10 mm Hg: AUROC = 0.97 ± 0.06). This was confirmed in the validation cohort (AUROC = 0.96 ± 0.01). The predictive index (constructed based on AST/ALT, spleen diameter, and TCDCA concentration) was able to distinguish clinically significant portal hypertension with 95% sensitivity and 76% specificity. CONCLUSIONS: TCDCA seems to be a promising noninvasive marker of clinically significant portal hypertension. Its predictive potential may be further enhanced when it is combined with both the AST/ALT ratio and spleen diameter.
BACKGROUND AND AIMS: Schistosoma mansoni infection is one of the worldwide leading causes of liver fibrosis and portal hypertension. The objective of this study was to evaluate whether polyhydroxylated bile acids (BAs), known to protect mice from the development of acquired cholestatic liver injury, counteract S. mansoni-induced inflammation and fibrosis. METHODS: Adult FVB/N wild type (WT) and Abcb11/Bsep-/- mice were infected with either 25 or 50 S. mansoni cercariae. Eight weeks post infection, effects on liver histology, serum biochemistry, gene expression profile of proinflammatory cytokines and fibrotic markers, hepatic hydroxyproline content and FACS analysis were performed. RESULTS: Bsep-/- mice infected with S. mansoni showed significantly less hepatic inflammation and tendentially less fibrosis compared to infected WT mice. Despite elevated alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels in infected Bsep-/- mice, inflammatory cells such as M2 macrophages and Mac-2/galectin-3+ cells were reduced in these animals. Accordingly, mRNA-expression levels of anti-inflammatory cytokines (IL-4 and IL-13) were increased in Bsep-/- mice upon infection. Furthermore, infected Bsep-/- mice exhibited decreased hepatic egg load and parasite fecundity, consequently affecting the worm reproduction rate. This outcome could arise from elevated serum BA levels and lower blood pH in Bsep-/- mice. CONCLUSIONS: The loss of Bsep and the resulting changes in bile acid composition and blood pH are associated with the reduction of parasite fecundity, thus attenuating the development of S. mansoni-induced hepatic inflammation and fibrosis.
- MeSH
- cytokiny metabolismus MeSH
- fertilita MeSH
- jaterní cirhóza prevence a kontrola etiologie MeSH
- játra patologie MeSH
- myši MeSH
- paraziti * MeSH
- Schistosoma mansoni MeSH
- schistosomiasis mansoni * komplikace MeSH
- zánět patologie MeSH
- žlučové kyseliny a soli metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- cvičení MeSH
- dietoterapie MeSH
- jaterní cirhóza diagnóza etiologie komplikace MeSH
- kyselina ursodeoxycholová aplikace a dávkování farmakologie terapeutické užití MeSH
- lidé MeSH
- nealkoholová steatóza jater * diagnóza etiologie terapie MeSH
- probiotika aplikace a dávkování terapeutické užití MeSH
- rizikové faktory MeSH
- střevní mikroflóra MeSH
- žlučové kyseliny a soli metabolismus terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- novinové články MeSH
- Klíčová slova
- kyselina obeticholová,
- MeSH
- antikoagulancia * terapeutické užití MeSH
- biliární cirhóza * farmakoterapie MeSH
- dítě MeSH
- dospělí MeSH
- duševní poruchy chemicky indukované MeSH
- epilepsie farmakoterapie MeSH
- komplikace těhotenství farmakoterapie MeSH
- kyselina valproová škodlivé účinky MeSH
- kyseliny cholové farmakologie terapeutické užití MeSH
- lidé MeSH
- mortalita MeSH
- nežádoucí účinky léčiv MeSH
- prenatální poškození * chemicky indukované MeSH
- prospektivní studie MeSH
- randomizované kontrolované studie jako téma MeSH
- těhotenství MeSH
- trombóza MeSH
- vena portae * patologie MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- těhotenství MeSH
Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multisystemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N-(3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1-, ALG1-, ALG8-, and PMM2-CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment.
- MeSH
- dítě MeSH
- glykosylace MeSH
- hydrolasy MeSH
- kojenec MeSH
- lidé MeSH
- Niemannova-Pickova nemoc typu C * MeSH
- oxysteroly * MeSH
- vakuolární protonové ATPasy * MeSH
- vrozené poruchy glykosylace * MeSH
- žlučové kyseliny a soli MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Carvedilol is a widely used beta-adrenoreceptor antagonist for multiple cardiovascular indications; however, it may induce cholestasis in patients, but the mechanism for this effect is unclear. Carvedilol also prevents the development of various forms of experimental liver injury, but its effect on nonalcoholic steatohepatitis (NASH) is largely unknown. In this study, we determined the effect of carvedilol (10 mg/kg/day p.o.) on bile formation and bile acid (BA) turnover in male C57BL/6 mice consuming either a chow diet or a western-type NASH-inducing diet. BAs were profiled by liquid chromatography-mass spectrometry and BA-related enzymes, transporters, and regulators were evaluated by western blot analysis and qRT-PCR. In chow diet-fed mice, carvedilol increased plasma concentrations of BAs resulting from reduced BA uptake to hepatocytes via Ntcp transporter downregulation. Inhibition of the β-adrenoreceptor-cAMP-Epac1-Ntcp pathway by carvedilol may be the post-transcriptional mechanism underlying this effect. In contrast, carvedilol did not worsen the deterioration of BA homeostasis accompanying NASH; however, it shifted the spectra of BAs toward more hydrophilic and less toxic α-muricholic and hyocholic acids. This positive effect of carvedilol was associated with a significant attenuation of liver steatosis, inflammation, and fibrosis in NASH mice. In conclusion, our results indicate that carvedilol may increase BAs in plasma by modifying their liver transport. In addition, carvedilol provided significant hepatoprotection in a NASH murine model without worsening BA accumulation. These data suggest beneficial effects of carvedilol in patients at high risk for developing NASH.
- MeSH
- homeostáza MeSH
- játra MeSH
- karvedilol farmakologie metabolismus MeSH
- lidé MeSH
- membránové transportní proteiny metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nealkoholová steatóza jater * metabolismus MeSH
- žlučové kyseliny a soli metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Malabsorpce žlučových kyselin (BAM – bile acid malabsorption) je výsledkem dysregulace enterohepatálního oběhu žlučových kyselin a jejich syntézy v játrech. Prevalence BAM je odhadována na 1 % všeobecné dospělé populace, patří mezi nejvíce opomíjené diagnózy. U osob splňujících diagnostická kritéria dráždivého tračníku se primární BAM vyskytuje u třetiny nemocných. U Crohnovy choroby s terminální ileitidou nebo po resekci terminálního ilea je BAM přítomna u 50–100 % pacientů. U onkologických pacientů s anamnézou radioterapie v oblasti pánve postihuje až polovinu nemocných. Zlatým standardem diagnostiky je SeHCAT test (75Selenium HomoCholic Acid Taurine test), nyní nově dostupný také v České republice. Hlavním dietním opatřením je omezení tuků v potravě. Základem farmakoterapie je podání sekvestrantů žlučových kyselin (v České republice je dostupný cholestyramin).
Bile acid malabsorption (BAM) is caused by dysregulation of enterohepatic circulation of bile acids and their synthesis in the liver. Estimated prevalence is about 1% of adult population. BAM has been substantially underdiagnosed. This condition can be present in one third of patients with diarrhoea-predominant irritable bowel syndrome and in 50–100% of Crohn‘s disease with ileitis or previously resected terminal ileum. Up to one half of oncology patients with pelvic radiotherapy suffer from BAM. SeHCAT test (75Selenium HomoCholic Acid Taurine test) is the gold diagnostic standard and the test has just become available in the Czech Republic. Low-fat diet is the most important dietary modification. Bile acids sequestrants (cholestyramine in the Czech Republic) are the crucial part of pharmacotherapy.
- Klíčová slova
- SeHCAT test,
- MeSH
- cholestyraminová pryskyřice MeSH
- diferenciální diagnóza MeSH
- lidé MeSH
- malabsorpční syndromy * diagnóza klasifikace terapie MeSH
- nádory * komplikace MeSH
- prevalence MeSH
- žlučové kyseliny a soli fyziologie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
