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Bile Acids Induce Neurite Outgrowth in Nsc-34 Cells via TGR5 and a Distinct Transcriptional Profile.

ABSTRACT: Increasing evidence supports a neuroprotective role for bile acids in major neurodegenerative disorders. We studied major human bile acids as signaling molecules for their two cellular receptors, farnesoid X receptor (FXR or NR1H4) and G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), as potential neurotrophic agents. Using quantitative image analysis, we found that 20 μM deoxycholic acid (DCA) could induce neurite outgrowth in NSC-34 cells that was comparable to the neurotrophic effects of the culture control 1 μM retinoic acid (RA), with lesser effects observed for chenodexoycholic acid (CDCA) at 20 μM, and similar though less robust neurite outgrowth in SH-SY5Y cells. Using chemical agonists and antagonists of FXR, LXR, and TGR5, we found that TGR5 agonism was comparable to DCA stimulation and stronger than RA, and that neither FXR nor liver X receptor (LXR) inhibition could block bile acid-induced neurite growth. RNA sequencing identified a core set of genes whose expression was regulated by DCA, CDCA, and RA. Our data suggest that bile acid signaling through TGR5 may be a targetable pathway to stimulate neurite outgrowth.

SUBMITTER: Ackerman HD

PROVIDER: S-EPMC9963315 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Bile Acids Induce Neurite Outgrowth in Nsc-34 Cells via TGR5 and a Distinct Transcriptional Profile.

Ackerman Hayley D HD Gerhard Glenn S GS

Pharmaceuticals (Basel, Switzerland) 20230124 2

Increasing evidence supports a neuroprotective role for bile acids in major neurodegenerative disorders. We studied major human bile acids as signaling molecules for their two cellular receptors, farnesoid X receptor (FXR or NR1H4) and G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), as potential neurotrophic agents. Using quantitative image analysis, we found that 20 μM deoxycholic acid (DCA) could induce neurite outgrowth in NSC-34 cells that was comparable to the neurotrophic effects ...[more]

PMID: 37259326

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Project description:Patients with cholestatic disease have increased systemic concentrations of bile acids (BAs) and profound pruritus. The G-protein-coupled BA receptor 1 TGR5 (encoded by GPBAR1) is expressed by primary sensory neurons; its activation induces neuronal hyperexcitability and scratching by unknown mechanisms. We investigated whether the transient receptor potential ankyrin 1 (TRPA1) is involved in BA-evoked, TGR5-dependent pruritus in mice.Co-expression of TGR5 and TRPA1 in cutaneous afferent neurons isolated from mice was analyzed by immunofluorescence, in situ hybridization, and single-cell polymerase chain reaction. TGR5-induced activation of TRPA1 was studied in in HEK293 cells, Xenopus laevis oocytes, and primary sensory neurons by measuring Ca(2+) signals. The contribution of TRPA1 to TGR5-induced release of pruritogenic neuropeptides, activation of spinal neurons, and scratching behavior were studied using TRPA1 antagonists or Trpa1(-/-) mice.TGR5 and TRPA1 protein and messenger RNA were expressed by cutaneous afferent neurons. In HEK cells, oocytes, and neurons co-expressing TGR5 and TRPA1, BAs caused TGR5-dependent activation and sensitization of TRPA1 by mechanisms that required G??, protein kinase C, and Ca(2+). Antagonists or deletion of TRPA1 prevented BA-stimulated release of the pruritogenic neuropeptides gastrin-releasing peptide and atrial natriuretic peptide B in the spinal cord. Disruption of Trpa1 in mice blocked BA-induced expression of Fos in spinal neurons and prevented BA-stimulated scratching. Spontaneous scratching was exacerbated in transgenic mice that overexpressed TRG5. Administration of a TRPA1 antagonist or the BA sequestrant colestipol, which lowered circulating levels of BAs, prevented exacerbated spontaneous scratching in TGR5 overexpressing mice.BAs induce pruritus in mice by co-activation of TGR5 and TRPA1. Antagonists of TGR5 and TRPA1, or inhibitors of the signaling mechanism by which TGR5 activates TRPA1, might be developed for treatment of cholestatic pruritus.

Project description:IntroductionSevere acute pancreatitis (SAP) is a crucial gastrointestinal disease characterized by systemic inflammatory responses and persistent multiple organ failure. The role of bile acids (BAs) in diverse inflammatory diseases is increasingly recognized as crucial, but the underlying role of BA conjugation remains elusive.ObjectivesOur study aim to investigate the potential role of conjugated bile acids in SAP and reveal the molecular mechanisms underlying its regulatory effects. We hypothesized that taurochenodeoxycholic acid (TCDCA) and glycochenodeoxycholic acid (GCDCA) could protect SAP through inhibiting the activation of NLRP3 inflammasomes via the TGR5 pathway in macrophages.MethodsTo test our hypothesis, we used BA-CoA: amino acid N-acyltransferase knockout (Baat-/-) mice and established SAP mouse models using caerulein- and sodium taurocholate- induced. We utilized a range of methods, including pathology sections, qRT-PCR, immunofluorescence, Western blotting, and ELISA, to identify the mechanisms of regulation.ResultsBA-CoA: Amino acid N-acyltransferase knockout (Baat-/-) mice significantly exacerbated pancreatitis by increasing pancreatic and systemic inflammatory responses and pancreatic damage in SAP mouse models. Moreover, the serum TCDCA levels in Baat-/- mice were lower than those in wild-type (WT) mice with or without SAP, and GCDCA and TCDCA showed stronger anti-inflammatory effects than chenodeoxycholic acid (CDCA) in vitro. TCDCA treatment alleviated SAP in a Takeda G protein-coupled receptor 5 and NOD-like receptor family, pyrin domain containing 3-dependent manner in vivo. Reinforcing our conclusions from the mouse study, clinical SAP patients exhibited decreased serum content of conjugated BAs, especially GCDCA, which was inversely correlated with the severity of systemic inflammatory responses.ConclusionConjugated bile acids significantly inhibit NLRP3 inflammasome activation by activating TGR5 pathway, thereby alleviating pancreatic immunopathology. The results provide new insights into the variability of clinical outcomes and paves the way for developing more effective therapeutic interventions for AP.

Dataset Information

Bile Acids Induce Neurite Outgrowth in Nsc-34 Cells via TGR5 and a Distinct Transcriptional Profile.

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Bile Acids Induce Neurite Outgrowth in Nsc-34 Cells via TGR5 and a Distinct Transcriptional Profile.

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