Role of the G Protein-Coupled Bile Acid Receptor TGR5 in Liver Damage

Reich, Maria; Klindt, Caroline; Deutschmann, K; Spomer, Lina; Häussinger, Dieter; Keitel, Verena

doi:10.1159/000450917

Cited by 42 publications

(29 citation statements)

References 42 publications

(99 reference statements)

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“…These cells express the G‐protein‐coupled BA receptor Takeda G protein‐coupled receptor 5 (TGR5), which can be activated by both conjugated and unconjugated BAs . Activation of TGR5 in macrophages reduces proinflammatory cytokines while maintaining anti‐inflammatory cytokine expression, thus promoting the development of an anti‐inflammatory macrophage phenotype . Furthermore, BAs inhibit the lipopolysaccharide (LPS)‐induced expression of the proinflammatory cytokines TNF‐α and IL‐6 in primary human macrophages .…”

Section: Discussionmentioning

confidence: 99%

“…A minor fraction of BAs escapes the enterohepatic circulation and reaches the systemic circulation where they regulate many processes, including lipid and glucose homeostasis, intestinal motility, inflammation and configuration and growth of the gut microbiome . A direct impact of BAs on the function of innate immune cells such as monocytes, macrophages and granulocytes has been reported .…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

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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“…Monocytes and macrophages express TGR5, the G-protein coupled bile acid receptor, that can be activated by both conjugated and unconjugated bile acids, with lithocholic acid(LCA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), and cholic acid (CA) being the most potent activators in descending order (50). Activation of TGR5 in macrophages reduces pro-inflammatory cytokines while maintaining anti-inflammatory cytokine expression thus promoting the development of an anti-inflammatory macrophage phenotype (88). In primary human macrophages, bile acids inhibit the LPS-induced expression of proinflammatory cytokines without affecting the expression of the anti-inflammatory cytokine IL-10, resulting in a macrophage phenotype with an increased IL-10/IL-12 ratio as well as a suppressed basal phagocytic activity (89).…”

Section: The Role Of Other Immune Cells In Cholestatic Liver Injurymentioning

confidence: 99%

Mechanisms of bile acid mediated inflammation in the liver

Cai

Boyer

2017

Molecular Aspects of Medicine

186

120

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Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury.

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“…TGR5 is presumed to have the heptahelical structure common to G‐protein‐coupled receptors. Ligand binding to TGR5 results in production of cAMP and release of Ca 2+ from the endoplasmic reticulum, and activation of downstream signaling cascades . Both unconjugated and conjugated bile salts activate TGR5.…”

Section: Bile Salt Receptors In the Enterohepatic Systemmentioning

confidence: 99%

Interactions between bile salts, gut microbiota, and hepatic innate immunity

Schubert

Damink

Bergen

et al. 2017

Immunological Reviews

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Bile salts are the water-soluble end products of hepatic cholesterol catabolism that are released into the duodenum and solubilize lipids due to their amphipathic structure. Bile salts also act as endogenous ligands for dedicated nuclear receptors that exert a plethora of biological processes, mostly related to metabolism. Bile salts are actively reclaimed in the distal part of the small intestine, released into the portal system, and subsequently extracted by the liver. This enterohepatic cycle is critically dependent on dedicated bile salt transporters. In the intestinal lumen, bile salts exert direct antimicrobial activity based on their detergent property and shape the gut microbiota. Bile salt metabolism by gut microbiota serves as a mechanism to counteract this toxicity and generates bile salt species that are distinct from those of the host. Innate immune cells of the liver play an important role in the early recognition and effector response to invading microbes. Bile salts signal primarily via the membrane receptor TGR5 and the intracellular farnesoid-x receptor, both present in innate immune cells. In this review, the interactions between bile salts, gut microbiota, and hepatic innate immunity are discussed.

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Role of the G Protein-Coupled Bile Acid Receptor TGR5 in Liver Damage

Cited by 42 publications

References 42 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

Mechanisms of bile acid mediated inflammation in the liver

Interactions between bile salts, gut microbiota, and hepatic innate immunity

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