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.
Mice
Animals
Bile Acids and Salts
/ metabolism
Arachidonate 5-Lipoxygenase
/ metabolism
Endothelial Cells
/ metabolism
Acetaminophen
/ toxicity
Receptors, G-Protein-Coupled
/ metabolism
Liver Diseases
/ metabolism
Chemical and Drug Induced Liver Injury
/ etiology
Leukotrienes
/ metabolism
GTP-Binding Proteins
/ metabolism
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
01 07 2023
01 07 2023
Historique:
received:
14
06
2022
accepted:
09
09
2022
medline:
21
6
2023
pubmed:
16
9
2022
entrez:
15
9
2022
Statut:
ppublish
Résumé
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 mutually interact in the development of DILI, we developed an orally active small molecule, CHIN117, that functions as a GPBAR1 agonist and CYSLTR1 antagonist. RNA-sequencing analysis of liver explants showed that acetaminophen (APAP) intoxication positively modulates the leukotriene pathway, CYSLTR1, 5-lipoxygenase, and 5-lipoxygenase activating protein, whereas GPBAR1 gene expression was unchanged. In mice, acute liver injury induced by orally dosing APAP (500 mg/kg) was severely exacerbated by Gpbar1 gene ablation and attenuated by anti-Cysltr1 small interfering RNA pretreatment. Therapeutic dosing of wild-type mice with CHIN117 reversed the liver damage caused by APAP and modulated up to 1300 genes, including 38 chemokines and receptors, that were not shared by dosing mice with a selective GPBAR1 agonist or CYSLTR1 antagonist. Coexpression of the two receptors was detected in liver sinusoidal endothelial cells (LSECs), monocytes, and Kupffer cells, whereas combinatorial modulation of CYSLTR1 and GPBAR1 potently reversed LSEC/monocyte interactions. CHIN117 reversed liver damage and liver fibrosis in mice administered CCl 4 . By genetic and pharmacological approaches, we demonstrated that GPBAR1 and CYSLTR1 mutually interact in the development of DILI. A combinatorial approach designed to activate GPBAR1 while inhibiting CYSLTR1 reverses liver injury in models of DILI.
Sections du résumé
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 mutually interact in the development of DILI, we developed an orally active small molecule, CHIN117, that functions as a GPBAR1 agonist and CYSLTR1 antagonist.
APPROACH AND RESULTS
RNA-sequencing analysis of liver explants showed that acetaminophen (APAP) intoxication positively modulates the leukotriene pathway, CYSLTR1, 5-lipoxygenase, and 5-lipoxygenase activating protein, whereas GPBAR1 gene expression was unchanged. In mice, acute liver injury induced by orally dosing APAP (500 mg/kg) was severely exacerbated by Gpbar1 gene ablation and attenuated by anti-Cysltr1 small interfering RNA pretreatment. Therapeutic dosing of wild-type mice with CHIN117 reversed the liver damage caused by APAP and modulated up to 1300 genes, including 38 chemokines and receptors, that were not shared by dosing mice with a selective GPBAR1 agonist or CYSLTR1 antagonist. Coexpression of the two receptors was detected in liver sinusoidal endothelial cells (LSECs), monocytes, and Kupffer cells, whereas combinatorial modulation of CYSLTR1 and GPBAR1 potently reversed LSEC/monocyte interactions. CHIN117 reversed liver damage and liver fibrosis in mice administered CCl 4 .
CONCLUSIONS
By genetic and pharmacological approaches, we demonstrated that GPBAR1 and CYSLTR1 mutually interact in the development of DILI. A combinatorial approach designed to activate GPBAR1 while inhibiting CYSLTR1 reverses liver injury in models of DILI.
Identifiants
pubmed: 36107019
pii: 01515467-202307000-00006
doi: 10.1002/hep.32787
doi:
Substances chimiques
leukotriene D4 receptor
LRF7RW46ID
Bile Acids and Salts
0
Arachidonate 5-Lipoxygenase
EC 1.13.11.34
Acetaminophen
362O9ITL9D
Receptors, G-Protein-Coupled
0
Leukotrienes
0
GTP-Binding Proteins
EC 3.6.1.-
Gpbar1 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
26-44Informations de copyright
Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
Références
Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullak‐Ublick GA, Watkins PB, et al. Drug‐induced liver injury. Nat Rev Dis Prim. 2019;5(1):58.
Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis. 2007;11(3):525–48, vi.
Donnelly MC, Davidson JS, Martin K, Baird A, Hayes PC, Simpson KJ. Acute liver failure in Scotland: changes in aetiology and outcomes over time (the Scottish Look‐Back Study). Aliment Pharmacol Ther. 2017;45(6):833–43.
Saito C, Zwingmann C, Jaeschke H. Novel mechanisms of protection against acetaminophen hepatotoxicity in mice by glutathione and N‐acetylcysteine. Hepatology. 2010;51(1):246–54.
Jeong HH, Cha K, Choi KH, So BH. Evaluation of cut‐off values in acute paracetamol overdose following the United Kingdom guidelines. BMC Pharmacol Toxicol. 2022;23(1):5.
Starkey Lewis P, Campana L, Aleksieva N, Cartwright JA, Mackinnon A, O'Duibhir E, et al. Alternatively activated macrophages promote resolution of necrosis following acute liver injury. J Hepatol. 2020;73(2):349–60.
Rolando N, Wade J, Davalos M, Wendon J, Philpott‐Howard J, Williams R. The systemic inflammatory response syndrome in acute liver failure. Hepatology. 2000;32(4 Pt 1):734–9.
Michael SL, Pumford NR, Mayeux PR, Niesman MR, Hinson JA. Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species. Hepatology. 1999;30(1):186–95.
Imaeda AB, Watanabe A, Sohail MA, Mahmood S, Mohamadnejad M, Sutterwala FS, et al. Acetaminophen‐induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J Clin Invest. 2009;119(2):305–14.
Biagioli M, Carino A, Fiorucci C, Marchianò S, Di Giorgio C, Bordoni M, et al. The bile acid receptor GPBAR1 modulates CCL2/CCR2 signaling at the liver sinusoidal/macrophage interface and reverses acetaminophen‐induced liver toxicity. J Immunol. 2020 Mar 25;204(9):2535–51.
Chen Y, Liu K, Zhang J, Hai Y, Wang P, Wang H, et al. c‐Jun NH(2) ‐terminal protein kinase phosphorylates the Nrf2‐ECH homology 6 domain of nuclear factor erythroid 2‐related factor 2 and downregulates cytoprotective genes in acetaminophen‐induced liver injury in mice. Hepatology. 2020;71(5):1787–801.
Arroyo V, Angeli P, Moreau R, Jalan R, Clària J, Trebicka J, et al. The systemic inflammation hypothesis: towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis. J Hepatol. 2021;74(3):670–85.
Bäck M, Dahlén SE, Drazen JM, Evans JF, Serhan CN, Shimizu T, et al. International Union of Basic and Clinical Pharmacology. LXXXIV: leukotriene receptor nomenclature, distribution, and pathophysiological functions. Pharmacol Rev. 2011;63(3):539–84.
Yokomizo T, Nakamura M, Shimizu T. Leukotriene receptors as potential therapeutic targets. J Clin Invest. 2018;128(7):2691–701.
Colazzo F, Gelosa P, Tremoli E, Sironi L, Castiglioni L. Role of the cysteinyl leukotrienes in the pathogenesis and progression of cardiovascular diseases. Mediators Inflamm. 2017;2017:2432958.
Pu S, Liu Q, Li Y, Li R, Wu T, Zhang Z, et al. Montelukast prevents mice against acetaminophen‐induced liver injury. Front Pharmacol. 2019;10:1070.
Keitel V, Reinehr R, Gatsios P, Rupprecht C, Görg B, Selbach O, et al. The G‐protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells. Hepatology. 2007;45(3):695–704.
Biagioli M, Carino A, Marchianò S, Roselli R, Di Giorgio C, Bordoni M, et al. Identification of cysteinyl‐leukotriene‐receptor 1 antagonists as ligands for the bile acid receptor GPBAR1. Biochem Pharmacol. 2020;177:113987.
Fiorucci S, Rapacciuolo P, Fiorillo B, Roselli R, Marchianò S, Di Giorgio C, et al. Discovery of a potent and orally active dual GPBAR1/CysLT1R modulator for the treatment of metabolic fatty liver disease. Front Pharmacol. 2022;13:858137.
Biagioli M, Carino A, Cipriani S, Francisci D, Marchianò S, Scarpelli P, et al. The bile acid receptor GPBAR1 regulates the M1/M2 phenotype of intestinal macrophages and activation of GPBAR1 rescues mice from Murine Colitis. J Immunol. 2017;199(2):718–33.
Biagioli M, Carino A, Fiorucci C, Marchianò S, Di Giorgio C, Roselli R, et al. GPBAR1 functions as gatekeeper for liver NKT cells and provides counterregulatory signals in mouse models of immune‐mediated hepatitis. Cell Mol Gastroenterol Hepatol. 2019;8(3):447–73.
Triantafyllou E, Woollard KJ, McPhail MJW, Antoniades CG, Possamai LA. The role of monocytes and macrophages in acute and acute‐on‐chronic liver failure. Front Immunol. 2018;9:2948.
Pholmoo N, Bunchorntavakul C. Characteristics and outcomes of acetaminophen overdose and hepatotoxicity in Thailand. J Clin Transl Hepatol. 2019;7(2):132–9.
Shetty S, Lalor PF, Adams DH. Liver sinusoidal endothelial cells—gatekeepers of hepatic immunity. Nat Rev Gastroenterol Hepatol. 2018;15(9):555–67.
Wang XK, Peng ZG. Targeting liver sinusoidal endothelial cells: an attractive therapeutic strategy to control inflammation in nonalcoholic fatty liver disease. Front Pharmacol. 2021;12:655557.
Kolios G, Valatas V, Kouroumalis E. Role of Kupffer cells in the pathogenesis of liver disease. World J Gastroenterol. 2006;12:7413–20.
Laskin DL, Gardner CR, Price VF, Jollow DJ. Modulation of macrophage functioning abrogates the acute hepatotoxicity of acetaminophen. Hepatology. 1995;21(4):1045–50.
Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ, et al. Depletion of liver Kupffer cells prevents the development of diet‐induced hepatic steatosis and insulin resistance. Diabetes. 2009;59(2):347–57.
Pendino KJ, Meidhof TM, Heck DE, Laskin JD, Laskin DL. Inhibition of macrophages with gadolinium chloride abrogates ozone‐induced pulmonary injury and inflammatory mediator production. Am J Respir Cell Mol Biol. 1995;13(2):125–32.
Andreata F, Blériot C, Di Lucia P, De Simone G, Fumagalli V, Ficht X, et al. Isolation of mouse Kupffer cells for phenotypic and functional studies. STAR Protoc. 2021;2(4):100831.
Fiorillo B, Sepe V, Conflitti P, Roselli R, Biagioli M, Marchianò S, et al. Structural basis for developing multitarget compounds acting on cysteinyl leukotriene receptor 1 and G‐protein‐coupled bile acid receptor 1. J Med Chem. 2021;64(22):16512–29.
Kawamata Y, Fujii R, Hosoya M, Harada M, Yoshida H, Miwa M, et al. A G protein‐coupled receptor responsive to bile acids. J Biol Chem. 2003;278(11):9435–40.
Biagioli M, Fiorucci S. Bile acid activated receptors: integrating immune and metabolic regulation in non‐alcoholic fatty liver disease. Liver Res. 2021;5(3):119–41.
Fiorucci S, Distrutti E, Carino A, Zampella A, Biagioli M. Bile acids and their receptors in metabolic disorders. Prog Lipid Res. 2021;82:101094.
Titos E, Clària J, Bataller R, Bosch‐Marcé M, Ginès P, Jiménez W, et al. Hepatocyte‐derived cysteinyl leukotrienes modulate vascular tone in experimental cirrhosis. Gastroenterology. 2000;119(3):794–805.
Duah E, Adapala RK, Al‐Azzam N, Kondeti V, Gombedza F, Thodeti CK, et al. Cysteinyl leukotrienes regulate endothelial cell inflammatory and proliferative signals through CysLT 2 and CysLT 1 receptors. Sci Rep. 2013;3:3274.
Fiorucci S, Biagioli M, Zampella A, Distrutti E. Bile acids activated receptors regulate innate immunity. Front Immunol. 2018;9:1853.
Cipriani S, Mencarelli A, Chini MG, Distrutti E, Renga B, Bifulco G, et al. The bile acid receptor GPBAR‐1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS One. 2011;6(10):e25637.
El‐Swefy S, Hassanen SI. Improvement of hepatic fibrosis by leukotriene inhibition in cholestatic rats. Ann Hepatol. 2009;8(1):41–9.
Carino A, Cipriani S, Marchianò S, Biagioli M, Santorelli C, Donini A, et al. BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis. Sci Rep. 2017;7:42801.
Liu ZX, Govindarajan S, Kaplowitz N. Innate immune system plays a critical role in determining the progression and severity of acetaminophen hepatotoxicity. Gastroenterology. 2004;127(6):1760–74.
Antoniades CG, Berry PA, Davies ET, Hussain M, Bernal W, Vergani D, et al. Reduced monocyte HLA‐DR expression: a novel biomarker of disease severity and outcome in acetaminophen‐induced acute liver failure. Hepatology. 2006;44(1):34–43.