2022
DOI: 10.1002/hep.32787
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Combinatorial targeting of G‐protein‐coupled bile acid receptor 1 and cysteinyl leukotriene receptor 1 reveals a mechanistic role for bile acids and leukotrienes in drug‐induced liver injury

Abstract: Background and Aim: Drug-induced liver injury (DILI) is a common disorder that involves both direct liver cell toxicity and immune activation.The bile acid receptor, G-protein-coupled bile acid receptor 1 (GPBAR1; Takeda G-protein-coupled receptor 5 [TGR5]), and cysteinyl leukotriene receptor (CYSLTR) 1 are G-protein-coupled receptors activated by bile acids and leukotrienes, exerting opposite effects on cell-to-cell adhesion, inflammation, and immune cell activation. To investigate whether GPBAR1 and CYSLTR1 … Show more

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Cited by 9 publications
(6 citation statements)
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“…149 As a potential treatment for DILI, the combinatorial G-proteincoupled bile acid receptor 1 (GPBAR1) agonist and cysteinyl leukotriene receptor 1 (CYSLTR1) antagonist, namely CHIN117, affected chemokine production and attenuated liver damage. 128 All these studies testify of a quickly evolving field of LSEC biology. The recent technological advances, such as multiomics, single cell and spatial omics, as well as the development of CRISPR/Cas9 transgenic mouse models, will lead the field toward better therapeutic strategies.…”
Section: Therapeuticsmentioning
confidence: 98%
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“…149 As a potential treatment for DILI, the combinatorial G-proteincoupled bile acid receptor 1 (GPBAR1) agonist and cysteinyl leukotriene receptor 1 (CYSLTR1) antagonist, namely CHIN117, affected chemokine production and attenuated liver damage. 128 All these studies testify of a quickly evolving field of LSEC biology. The recent technological advances, such as multiomics, single cell and spatial omics, as well as the development of CRISPR/Cas9 transgenic mouse models, will lead the field toward better therapeutic strategies.…”
Section: Therapeuticsmentioning
confidence: 98%
“…127 DILI is also promoted by the leukotriene pathway, from which cysteinyl leukotriene receptor 1 (CYSLTR1) is expressed in several liver cell types, including LSECs. 128 Anti-Cysltr1 small interfering RNA pretreatment, in combination with a G-protein-coupled bile acid receptor 1 (GPBAR1) agonist, reversed LSEC/monocyte interactions and liver injury. 128 The interaction of LSECs with Kupffer cells (KCs) is crucial to maintain liver health, as the depletion of KCs prior to acetaminophen insult aggravated DILI-mediated LSEC injury and enhanced the expression of cellular adhesion molecules in LSECs.…”
Section: Accepted Manuscriptmentioning
confidence: 99%
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“… 66 synthesized ligand compound 4b with strong TGR5 agonist activity by using TMN (5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene) as the skeleton, which provides a potential drug choice for the treatment of dyslipidaemia. In addition, TGR5 agonists in the past 5 years are listed in Table 1 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 .…”
Section: Natural and Synthetic Ligands Of Tgr5mentioning
confidence: 99%
“…Alcohol, drugs and viral infections have been shown to induce liver fibrosis because these stimuli cause repeated damage to hepatocytes, which stimulates HSC activation (Tsuchida and Friedman, 2017 ). In addition, chronic carbon tetrachloride (CCl 4 ) is commonly used to induce hepatocyte injury and thus mimics the process of liver fibrosis, and CCl 4 -treated mice exhibit dramatic upregulation of TGF-β and activation of HSCs (Biagioli et al, 2022 ).…”
Section: Introductionmentioning
confidence: 99%