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
• komentáře MeSH
• práce podpořená grantem MeSH
• Názvy látek
• farnesoid X-activated receptor MeSH Prohlížeč
• GPBAR1 protein, human MeSH Prohlížeč
• receptory cytoplazmatické a nukleární * MeSH
• receptory spřažené s G-proteiny * MeSH
• transkripční faktory MeSH
• žlučové kyseliny a soli * MeSH

The Takeda G protein-coupled receptor 5 (TGR5), also known as GPBAR1 (G protein-coupled bile acid receptor), is a membrane-type bile acid receptor that regulates blood glucose levels and energy expenditure. These essential functions make TGR5 a promising target for the treatment of type 2 diabetes and metabolic disorders. Currently, most research on developing TGR5 agonists focuses on modifying the structure of bile acids, which are the endogenous ligands of TGR5. However, TGR5 agonists with nonsteroidal structures have not been widely explored. This study aimed at discovering new TGR5 agonists using bile acid derivatives as a basis for a computational approach. We applied a combination of pharmacophore-based, molecular docking, and molecular dynamic (MD) simulation to identify potential compounds as new TGR5 agonists. Through pharmacophore screening and molecular docking, we identified 41 candidate compounds. From these, five candidates were selected based on criteria including pharmacophore features, a docking score of less than 9.2 kcal/mol, and similarity in essential interaction patterns with a reference ligand. Biological assays of the five hits confirmed that Hit-3 activates TGR5 similarly to the bile acid control. This was supported by MD simulation results, which indicated that a hydrogen bond interaction with Tyr240 is involved in TGR5 activation. Hit-3 (CSC089939231) represents a new nonsteroidal lead that can be further optimized to design potent TGR5 agonists.

• Klíčová slova
• INT‐777, TGR5, molecular docking, nonbile acid, pharmacophore,
• MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• objevování léků MeSH
• receptory spřažené s G-proteiny * agonisté   metabolismus   MeSH
• simulace molekulární dynamiky * MeSH
• simulace molekulového dockingu * MeSH
• vztahy mezi strukturou a aktivitou MeSH
• žlučové kyseliny a soli chemie   metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• GPBAR1 protein, human MeSH Prohlížeč
• ligandy MeSH
• receptory spřažené s G-proteiny * MeSH
• žlučové kyseliny a soli MeSH

Stress of endoplasmic reticulum (ERS) is one of the molecular triggers of adipocyte dysfunction and chronic low inflammation accompanying obesity. ERS can be alleviated by chemical chaperones from the family of bile acids (BAs). Thus, two BAs currently used to treat cholestasis, ursodeoxycholic and tauroursodeoxycholic acid (UDCA and TUDCA), could potentially lessen adverse metabolic effects of obesity. Nevertheless, BAs effects on human adipose cells are mostly unknown. They could regulate gene expression through pathways different from their chaperone function, namely through activation of farnesoid X receptor (FXR) and TGR5, G-coupled receptor. Therefore, this study aimed to analyze effects of UDCA and TUDCA on human preadipocytes and differentiated adipocytes derived from paired samples of two distinct subcutaneous adipose tissue depots, abdominal and gluteal. While TUDCA did not alter proliferation of cells from either depot, UDCA exerted strong anti-proliferative effect. In differentiated adipocytes, acute exposition to neither TUDCA nor UDCA was able to reduce effect of ERS stressor tunicamycin. However, exposure of cells to UDCA during whole differentiation process decreased expression of ERS markers. At the same time however, UDCA profoundly inhibited adipogenic conversion of cells. UDCA abolished expression of PPARγ and lipogenic enzymes already in the early phases of adipogenesis. This anti-adipogenic effect of UDCA was not dependent on FXR or TGR5 activation, but could be related to ability of UDCA to sustain the activation of ERK1/2 previously linked with PPARγ inactivation. Finally, neither BAs did lower expression of chemokines inducible by TLR4 pathway, when UDCA enhanced their expression in gluteal adipocytes. Therefore while TUDCA has neutral effect on human preadipocytes and adipocytes, the therapeutic use of UDCA different from treating cholestatic diseases should be considered with caution because UDCA alters functions of human adipose cells.

• MeSH
• adipogeneze účinky léků   MeSH
• aktivace enzymů účinky léků   MeSH
• buněčná diferenciace účinky léků   MeSH
• cytokiny genetika   MeSH
• kyselina taurochenodeoxycholová farmakologie   MeSH
• kyselina ursodeoxycholová farmakologie   MeSH
• lidé MeSH
• mitogenem aktivovaná proteinkinasa 1 metabolismus   MeSH
• mitogenem aktivovaná proteinkinasa 3 metabolismus   MeSH
• podkožní tuk cytologie   MeSH
• proliferace buněk účinky léků   MeSH
• regulace genové exprese účinky léků   MeSH
• stres endoplazmatického retikula účinky léků   MeSH
• tukové buňky cytologie   účinky léků   metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• kyselina taurochenodeoxycholová MeSH
• kyselina ursodeoxycholová MeSH
• mitogenem aktivovaná proteinkinasa 1 MeSH
• mitogenem aktivovaná proteinkinasa 3 MeSH
• ursodoxicoltaurine MeSH Prohlížeč

Bile acids (BA), for decades considered only to have fat-emulsifying functions in the gut lumen, have recently emerged as novel cardio-metabolic modulators. They have real endocrine effects, acting via multiple intracellular receptors in various organs and tissues. BA affect energy homeostasis through the modulation of glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor (FXR), as well as the cytoplasmic membrane G protein-coupled BA receptor TGR5 in a variety of tissues; although numerous other intracellular targets of BA are also in play.The roles of BA in the pathogenesis of diabetes, obesity, metabolic syndrome, and cardiovascular diseases are seriously being considered, and BA and their derivatives seem to represent novel potential therapeutics to treat these diseases of civilization.

• Klíčová slova
• Bile acids. Diabetes. Obesity. Metabolic syndrome. Cardiovascular diseases.,
• MeSH
• hypoglykemika terapeutické užití   MeSH
• hypolipidemika terapeutické užití   MeSH
• kardiovaskulární látky terapeutické užití   MeSH
• kardiovaskulární nemoci farmakoterapie   metabolismus   MeSH
• látky proti obezitě terapeutické užití   MeSH
• lidé MeSH
• metabolické nemoci farmakoterapie   metabolismus   MeSH
• metabolismus lipidů účinky léků   MeSH
• objevování léků MeSH
• probiotika terapeutické užití   MeSH
• signální transdukce účinky léků   MeSH
• střeva účinky léků   mikrobiologie   MeSH
• střevní mikroflóra MeSH
• střevní sliznice metabolismus   MeSH
• žlučové kyseliny a soli metabolismus   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• hypoglykemika MeSH
• hypolipidemika MeSH
• kardiovaskulární látky MeSH
• látky proti obezitě MeSH
• žlučové kyseliny a soli MeSH

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.

• Klíčová slova
• bariatric surgery, bile acids, diabetes, energy homeostasis, obesity,
• 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
• Názvy látek
• farnesoid X-activated receptor MeSH Prohlížeč
• glukosa MeSH
• GPBAR1 protein, human MeSH Prohlížeč
• inkretiny MeSH
• receptory cytoplazmatické a nukleární MeSH
• receptory spřažené s G-proteiny MeSH
• žlučové kyseliny a soli MeSH

Bile acid malabsorption (BAM) is a common but an underestimated and often neglected sign of inflammatory bowel diseases (IBDs), especially those affecting the distal ileum. Clinically relevant BAM is most often present in patients with Crohn's ileitis and particularly in ileal-resected Crohn's disease patients. However, deterioration of bile acid (BA) metabolism occurs also in patients with IBD without ileal disease or in those in clinical remission, and the role of BAM in these patients is not well appreciated by clinicians. In a majority of cases, BAM in IBD is caused by impaired conjugated BA reabsorption, mediated by apical sodium/BA cotransporting polypeptide, localized at the luminal surface of the ileal enterocytes. As a consequence, numerous pathological sequelae may occur, including the malfunction of lipid digestion with clinical steatorrhea, impaired intestinal motility, and/or significant changes in the intestinal microflora environment. In this review, a detailed description of the pathophysiological mechanisms of BAM-related diarrhea is presented. Although BAM is present in a significant number of patients with Crohn's disease, its laboratory assessment is not routinely included in diagnostic workups, partially because of costs, logistical reasons, or the unavailability of the more sophisticated laboratory equipment needed. Simultaneously, novel findings related to the effects of the BA signaling pathways on immune functions (mediated through TGR5, cell membrane G protein-coupled BA receptor 1, nuclear farnesoid X receptor, nuclear pregnane X receptor, or nuclear vitamin D receptor) are discussed along with intestinal metabolism in its relationship to the pathogenesis of IBD.

• MeSH
• idiopatické střevní záněty etiologie   patologie   MeSH
• lidé MeSH
• prognóza MeSH
• průjem komplikace   patologie   MeSH
• steatorea komplikace   patologie   MeSH
• žlučové kyseliny a soli metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• žlučové kyseliny a soli MeSH