Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often associated with underlying inflammatory bowel disease (IBD). This study investigates how PSC predisposes individuals to altered inflammatory immune responses compared with IBD alone. A case-control study was conducted with a cohort of 75 patients, including 16 with PSC (14 with concomitant IBD), 39 with IBD alone, and 20 controls. Serum bile acid profile, proteomic analysis, and immune-related gene expression in the colon tissue were examined. Colonic tissue from PSC patients exhibited up-regulation of immune regulation and inflammatory signaling mRNA markers, including LGR5, IL-8, CCL2, COX2, TWIST1, and SNAIL. Additionally, PSC patients displayed a distinct proinflammatory serum proteomic signature and moderate elevation of some bile acids, such as glycochenodeoxycholic acid (GCDCA). Co-incubation of human-derived monocytes with GCDCA partially replicated the inflammatory profile observed in PSC. These findings suggest that circulating bile acids modulate the peripheral immune system proinflammatory response, contributing to the unique PSC phenotype.

• Klíčová slova
• GCDCA, IBD, PSC, bile acids, immune response,
• MeSH
• dospělí MeSH
• idiopatické střevní záněty * imunologie   komplikace   krev   genetika   MeSH
• kolon metabolismus   imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• monocyty imunologie   metabolismus   MeSH
• proteomika metody   MeSH
• sklerozující cholangitida * imunologie   krev   komplikace   genetika   MeSH
• studie případů a kontrol MeSH
• žlučové kyseliny a soli * krev   imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• žlučové kyseliny a soli * MeSH

Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related nuclear receptors with overlapping regulatory functions in xenobiotic clearance but distinct roles in endobiotic metabolism. Car activation has been demonstrated to ameliorate hypercholesterolemia by regulating cholesterol metabolism and bile acid elimination, whereas PXR activation is associated with hypercholesterolemia and liver steatosis. Here we show a human CAR agonist/PXR antagonist, MI-883, which effectively regulates genes related to xenobiotic metabolism and cholesterol/bile acid homeostasis by leveraging CAR and PXR interactions in gene regulation. Through comprehensive analyses utilizing lipidomics, bile acid metabolomics, and transcriptomics in humanized PXR-CAR-CYP3A4/3A7 mice fed high-fat and high-cholesterol diets, we demonstrate that MI-883 significantly reduces plasma cholesterol levels and enhances fecal bile acid excretion. This work paves the way for the development of ligands targeting multiple xenobiotic nuclear receptors. Such ligands hold the potential for precise modulation of liver metabolism, offering new therapeutic strategies for metabolic disorders.

• MeSH
• cholesterol metabolismus   krev   MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• dieta s vysokým obsahem tuků škodlivé účinky   MeSH
• hypercholesterolemie * farmakoterapie   metabolismus   etiologie   MeSH
• hypolipidemika * farmakologie   terapeutické užití   MeSH
• játra metabolismus   účinky léků   MeSH
• konstitutivní androstanový receptor MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• pregnanový X receptor * antagonisté a inhibitory   metabolismus   genetika   MeSH
• receptory cytoplazmatické a nukleární * agonisté   metabolismus   genetika   antagonisté a inhibitory   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
• Názvy látek
• cholesterol MeSH
• cytochrom P-450 CYP3A MeSH
• hypolipidemika * MeSH
• konstitutivní androstanový receptor MeSH
• pregnanový X receptor * MeSH
• receptory cytoplazmatické a nukleární * MeSH
• žlučové kyseliny a soli MeSH

(1) Objectives: Intestinal failure in home parenteral nutrition patients (HPNPs) results in oxidative stress and liver damage. This study investigated how a high dose of fish oil (FO) added to various lipid emulsions influences antioxidant status and liver function markers in HPNPs. (2) Methods: Twelve HPNPs receiving Smoflipid for at least 3 months were given FO (Omegaven) for a further 4 weeks. Then, the patients were randomized to subsequently receive Lipoplus and ClinOleic for 6 weeks or vice versa plus 4 weeks of Omegaven after each cycle in a crossover design. Twelve age- and sex-matched healthy controls (HCs) were included. (3) Results: Superoxide dismutase (SOD1) activity and oxidized-low-density lipoprotein concentration were higher in all baseline HPN regimens compared to HCs. The Omegaven lowered SOD1 compared to baseline regimens and thus normalized it toward HCs. Lower paraoxonase 1 activity and fibroblast growth factor 19 (FGF19) concentration and, on the converse, higher alkaline phosphatase activity and cholesten concentration were observed in all baseline regimens compared to HCs. A close correlation was observed between FGF19 and SOD1 in baseline regimens. (4) Conclusions: An escalated dose of FO normalized SOD1 activity in HPNPs toward that of HCs. Bile acid metabolism was altered in HPNPs without signs of significant cholestasis and not affected by Omegaven.

• Klíčová slova
• bile acids, chronic intestinal failure, fibroblast growth factor 19, liver function tests, oxidative stress, short bowel syndrome,
• MeSH
• cholestáza * MeSH
• lidé MeSH
• parenterální výživa doma * metody   MeSH
• rybí oleje MeSH
• sójový olej MeSH
• superoxiddismutasa 1 MeSH
• tukové emulze intravenózní MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• rybí oleje MeSH
• sójový olej MeSH
• superoxiddismutasa 1 MeSH
• tukové emulze intravenózní MeSH

Zucker fatty (fa/fa) rats represent a well-established and widely used model of genetic obesity. Because previous metabolomic studies have only been published for young fa/fa rats up to 20 weeks of age, which can be considered early maturity in male fa/fa rats, the aim of our work was to extend the metabolomic characterization to significantly older animals. Therefore, the urinary profiles of obese fa/fa rats and their lean controls were monitored using untargeted NMR metabolomics between 12 and 40 weeks of age. At the end of the experiment, the rats were also characterized by NMR and LC-MS serum analysis, which was supplemented by a targeted LC-MS analysis of serum bile acids and neurotransmitters. The urine analysis showed that most of the characteristic differences detected in young obese fa/fa rats persisted throughout the experiment, primarily through a decrease in microbial co-metabolite levels, the upregulation of the citrate cycle, and changes in nicotinamide metabolism compared with the age-related controls. The serum of 40-week-old obese rats showed a reduction in several bile acid conjugates and an increase in serotonin. Our study demonstrated that the fa/fa model of genetic obesity is stable up to 40 weeks of age and is therefore suitable for long-term experiments.

• Klíčová slova
• LC-MS, NMR, fa/fa rats, genetic obesity, metabolomics,
• Publikační typ
• časopisecké články MeSH

Dyslipidemia is common among patients on hemodialysis, but its etiology is not fully understood. Although changes in cholesterol homeostasis and fatty acid metabolism play an important role during dialysis, the interaction of these metabolic pathways has yet to be studied in sufficient detail. In this study, we enrolled 26 patients on maintenance hemodialysis treatment (high-volume hemodiafiltration, HV HDF) without statin therapy (17 men/9 women) and an age/gender-matched group of 26 individuals without signs of nephropathy. The HV-HDF group exhibited more frequent signs of cardiovascular disease, disturbed saccharide metabolism, and altered lipoprotein profiles, manifesting in lower HDL-C, and raised concentrations of IDL-C and apoB-48 (all p < 0.01). HV-HDF patients had higher levels of campesterol (p < 0.01) and β-sitosterol (p = 0.06), both surrogate markers of cholesterol absorption and unchanged lathosterol concentrations. Fatty acid (FA) profiles were changed mostly in cholesteryl esters, with a higher content of saturated and n-3 polyunsaturated fatty acids (PUFA) in the HV-HDF group. However, n-6 PUFA in cholesteryl esters were less abundant (p < 0.001) in the HV-HDF group. Hemodialysis during end-stage kidney disease induces changes associated with higher absorption of cholesterol and disturbed lipoprotein metabolism. Changes in fatty acid metabolism reflect the combined effect of renal insufficiency and its comorbidities, mostly insulin resistance.

• Klíčová slova
• chronic kidney disease, fatty acids, hemodialysis, hypolipidemic treatment, non-cholesterol sterols,
• Publikační typ
• časopisecké články MeSH