Developments in bile salt based therapies: A critical overview

Donkers, Joanne M.; Abbing, Reinout L.P. Roscam; Graaf, Stan F.J. van de

doi:10.1016/j.bcp.2018.12.018

Cited by 62 publications

(44 citation statements)

References 171 publications

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“…Bile acids (BAs) have received considerable interest due to their critical role in metabolic modulation. Dysregulated metabolism and signaling of BAs are suggested to play a role in several diseases, such as dyslipidemia, fatty liver disease, diabetes, obesity and atherosclerosis , as well as in inflammatory diseases . The two primary BAs, cholic acid (CA) and chenodeoxycholic acid (CDCA), are generated by the liver hepatocytes from cholesterol breakdown .…”

Section: Introductionmentioning

confidence: 99%

MAIT cell activation in adolescents is impacted by bile acid concentrations and body weight

Mendler

Pierzchalski

Bauer

et al. 2020

Clinical and Experimental Immunology

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Bile acids (BAs) are produced by liver hepatocytes and were recently shown to exert functions additional to their well-known role in lipid digestion. As yet it is not known whether the mucosal-associated invariant T (MAIT) cells, which represent 10-15% of the hepatic T cell population, are affected by BAs. The focus of the present investigation was on the association of BA serum concentration with MAIT cell function and inflammatory parameters as well as on the relationship of these parameters to body weight. Blood samples from 41 normal weight and 41 overweight children of the Lifestyle Immune System Allergy (LISA) study were analyzed with respect to MAIT cell surface and activation markers [CD107a, CD137, CD69, interferon (IFN)-γ, tumor necrosis factor (TNF)-α] after Escherichia coli stimulation, mRNA expression of promyelocytic leukemia zinc finger protein (PLZF) and major histocompatibility complex class I-related gene protein (MR1), the inflammatory markers C-reactive protein (CRP), interleukin (IL)-8 and macrophage inflammatory protein (MIP)-1α as well as the concentrations of 13 conjugated and unconjugated BAs. Higher body weight was associated with reduced MAIT cell activation and expression of natural killer cell marker (NKp80) and chemokine receptor (CXCR3). BA concentrations were positively associated with the inflammatory parameters CRP, IL-8 and MIP-1α, but were negatively associated with the number of activated MAIT cells and the MAIT cell transcription factor PLZF. These relationships were exclusively found with conjugated BAs. BA-mediated inhibition of MAIT cell activation was confirmed in vitro. Thus, conjugated BAs have the capacity to modulate the balance between pro-and anti-inflammatory immune responses.

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Section: Introductionmentioning

confidence: 99%

MAIT cell activation in adolescents is impacted by bile acid concentrations and body weight

Mendler

Pierzchalski

Bauer

et al. 2020

Clinical and Experimental Immunology

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“…BA signaling and BA pool composition are increasingly considered as crucial for intestine and liver pathophysiology [14,15,16,24,25], and therapeutic strategies targeting BA and their receptors begin to emerge [26]. This is particularly true in the field of metabolic diseases such as obesity and diabetes [17], as well as for cholestatic liver diseases [27].…”

Section: Discussionmentioning

confidence: 99%

Bile Acid pool composition and Gallbladder function are controlled by TGR5 to protect the liver against Bile Acid overload

Bidault

Merlen

Glénisson

et al. 2020

Preprint

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Backgrounds & AimsAs the bile acid (BA) pool composition is of major impact on liver pathophysiology, we studied its regulation by the BA receptor TGR5, promoting hepatoprotection against BA overload.MethodsWT, total and hepato-specific TGR5-KO, and TGR5-overexpressing mice were used in: partial and 90% extended hepatectomies (EH) upon normal, ursodeoxycholic acid (UDCA)- or cholestyramine (CT)-enriched diet, bile duct ligation (BDL), cholic acid (1%)-enriched diet, and TGR5 agonist (RO) treatments. We thereby studied TGR5 impact on: BA pool composition, liver injury, regeneration and survival. Particular focus was made on gut microbiota (GM) and gallbladder (GB) function analysis. BA pool composition was analyzed in patients undergoing major hepatectomy.ResultsThe TGR5-KO hyperhydrophobic BA pool was not related to BA synthesis alteration, nor to the TGR5-KO GM dysbiosis, as supported by hepatocyte-specific KO mice and cohousing experiments. The TGR5-dependent control of GB dilatation was crucial for BA pool composition, as determined by experiments including RO treatment +/− cholecystectomy. The poor TGR5-KO post-EH survival rate, related with exacerbated peribiliary necrosis and BA overload, was improved by shifting the BA pool towards a more hydrophilic composition (CT and UDCA treatments). After either BDL or CA-enriched diet +/− cholecystectomy, we found that GB dilatation had strong TGR5-dependent hepatoprotective properties. In patients, a more hydrophobic BA pool was correlated with an unfavorable outcome after hepatectomy.ConclusionBA pool composition is crucial for hepatoprotection in mice and humans. We point TGR5 as a key regulator of BA profile and thereby as a potential hepatoprotective target under BA overload conditions.Lay summaryThrough multiple in vivo experimental approaches in mice, together with a patients study, this work brings some new light on the relationships between biliary homeostasis, gallbladder function and liver protection. We showed that the bile acid pool composition is crucial for optimal liver repair, not only in mice but also in human patients undergoing major hepatectomy.

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“…ASBT dysfunction leads to more bile acids in the colon, leading to diarrhea, gallstone disease, hypertriglyceridemia, or even colon cancer [4]. However, the inhibition of ASBT, as well as NTCP, can be a treatment option for hypercholesterolemia and cholestasis, as well as nonalcoholic fatty liver [5,21,22]. Therefore, determining the drug-drug interaction of ASBT can help in medication choices.…”

Section: Discussionmentioning

confidence: 99%

Apical Sodium-Dependent Bile Acid Cotransporter, A Novel Transporter of Indocyanine Green, and Its Application in Drug Screening

Hsiao

2020

IJMS

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Bile acid plays critical roles in the elimination of inorganic compounds such as bilirubin, heavy metals, and drug metabolites. Apical sodium-dependent bile acid cotransporter (ASBT), a solute carrier membrane transport protein, transports bile acids. Several inhibitors of ASBT have been evaluated in clinical trials. Sodium taurocholate cotransporting polypeptide (NTCP), belonging to the same family as ASBT, has fluorescein 5(6)-isothiocyanate (FITC) and indocyanine green (ICG) transportability. ICG, a Food and Drug Administration-approved fluorophore at near-infrared range, has perfect optical characteristics, so it can be applied in cell tracking and drug screening. In this study, ASBT and NTCP were transduced into the HT-1080 cell line. Nude mice were subcutaneously xenografted with control and ASBT-expressing cells. ICG transportability was observed through flow cytometry, fluorescent microscopy, multi-mode plate readers, and an in vivo imaging system. Several molecules, including taurocholate, sodium deoxycholate, cyclosporine A, nifedipine, and Primovist, were used to evaluate an in vitro drug-screening platform by using the combination of ICG and ASBT through flow cytometry. ICG and FITC were validated and shown to be transported by ASBT. NTCP had a higher ICG intensity compared with ASBT. For cell tracking, the ASBT xenograft had similar ICG signals as the control. For a drug-screening platform, the ICG intensity decreased with 186 μM taurocholate (56.8%), deoxycholate (83.8%), and increased with nifedipine (133.2%). These findings are suggestive of opportunities for the high-throughput drug screening of cholestasis and other diseases that are related to the dynamics of bile acid reabsorption.

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Developments in bile salt based therapies: A critical overview

Cited by 62 publications

References 171 publications

MAIT cell activation in adolescents is impacted by bile acid concentrations and body weight

MAIT cell activation in adolescents is impacted by bile acid concentrations and body weight

Bile Acid pool composition and Gallbladder function are controlled by TGR5 to protect the liver against Bile Acid overload

Apical Sodium-Dependent Bile Acid Cotransporter, A Novel Transporter of Indocyanine Green, and Its Application in Drug Screening

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