Letter to the editor

TGR5 regulates portal perfusion pressure of the liver

Ahmed Ghallab1[*]

1Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt

EXCLI J 2019;18:Doc1107

 



Dear Editor,

Recently, Klindt and colleagues from the University of Düsseldorf published a study on the role of the bile acid receptor TGR5 in modulating portal pressure (Klindt et al., 2019[14]). TGR5 is activated by bile acids, leads to an intracellular increase of cAMP (Kawamata et al., 2003[10]; Keitel et al., 2019[13]; Maruyama et al., 2002[15]) and mediates cytoprotective effects (Keitel et al., 2009[11], 2015[12]; Merlen et al., 2020[16]; Perino and Schoonjans, 2015[18]; Perino et al., 2014[17]; Guo et al., 2016[5]). In their present study, the authors present a concept according to which activation of TGR5 in sinusoidal endothelial cells of the liver blocks the release of endothelin-1. Endothelin-1 is known to cause contraction of hepatic stellate cells via the ETA receptor. Therefore, endothelin-1 leads to a narrowing of the liver sinusoids and an increase of portal pressure (Klindt et al., 2019[14]). Moreover, activation of TGR5 in hepatic stellate cells leads to internalization of the ETAR that also reduces the responsiveness to the contractile effect of endothelin-1.

The prevalence of liver diseases currently increases (Jansen et al., 2017[9]; Ekhlasi et al., 2017[1]; Hudert et al., 2019[8]) and a better understanding of the responsible mechanisms is urgently needed to identify better strategies for therapeutic intervention (Svinka et al., 2017[20]; Godoy et al., 2016[3]; Ghallab et al., 2016[2]; Gogiashvili et al., 2017[4]). A particular challenge is that different cell types in the liver communicate in a complex manner, which leads to a situation, where the result of interventions is difficult to predict (Hoehme et al., 2010[7]; Hammad et al., 2014[6]; Schenk et al., 2017[19]). The present study of Klindt and colleagues represents an important milestone in understanding the pathophysiology of increased portal pressure.

Conflict of interest

The author declares no conflict of interest.

 

References

1. Ekhlasi G, Zarrati M, Agah S, Hosseini AF, Hosseini S, Shidfar S, et al. Effects of symbiotic and vitamin E supplementation on blood pressure, nitric oxide and inflammatory factors in non-alcoholic fatty liver disease. EXCLI J. 2017;16:278-90. doi: 10.17179/excli2016-846.
2. Ghallab A, Cellière G, Henkel SG, Driesch D, Hoehme S, Hofmann U, et al. Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases. J Hepatol. 2016;64:860-71. doi: 10.1016/j.jhep.2015.11.018.
3. Godoy P, Widera A, Schmidt-Heck W, Campos G, Meyer C, Cadenas C, et al. Gene network activity in cultivated primary hepatocytes is highly similar to diseased mammalian liver tissue. Arch Toxicol. 2016;90:2513-29. doi: 10.1007/s00204-016-1761-4.
4. Gogiashvili M, Edlund K, Gianmoena K, Marchan R, Brik A, Andersson JT, et al. Metabolic profiling of ob/ob mouse fatty liver using HR-MAS 1H-NMR combined with gene expression analysis reveals alterations in betaine metabolism and the transsulfuration pathway. Anal Bioanal Chem. 2017;409:1591-606. doi: 10.1007/s00216-016-0100-1.
5. Guo C, Xie S, Chi Z, Zhang J, Liu Y, Zhang L, et al. Bile acids control inflammation and metabolic disorder through inhibition of NLRP3 inflammasome. Immunity. 2016;45:802-16. doi: 10.1016/j.immuni.2016.09.008.
6. Hammad S, Hoehme S, Friebel A, von Recklinghausen I, Othman A, Begher-Tibbe B, et al. Protocols for staining of bile canalicular and sinusoidal networks of human, mouse and pig livers, three-dimensional reconstruction and quantification of tissue microarchitecture by image processing and analysis. Arch Toxicol. 2014;88:1161-83. doi: 10.1007/s00204-014-1243-5.
7. Hoehme S, Brulport M, Bauer A, Bedawy E, Schormann W, Hermes M, et al. Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Proc Natl Acad Sci U S A. 2010;107:10371-6. doi: 10.1073/pnas.0909374107.
8. Hudert CA, Selinski S, Rudolph B, Bläker H, Loddenkemper C, Thielhorn R, et al. Genetic determinants of steatosis and fibrosis progression in paediatric non-alcoholic fatty liver disease. Liver Int. 2019;39:540-56. doi: 10.1111/liv.14006.
9. Jansen PL, Ghallab A, Vartak N, Reif R, Schaap FG, Hampe J, et al. The ascending pathophysiology of cholestatic liver disease. Hepatology. 2017;65:722-38. doi: 10.1002/hep.28965.
10. 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;278:9435-40. doi: 10.1074/jbc.M209706200.
11. Keitel V, Cupisti K, Ullmer C, Knoefel WT, Kubitz R, Häussinger D. The membrane-bound bile acid receptor TGR5 is localized in the epithelium of human gallbladders. Hepatology. 2009;50:861-70. doi: 10.1002/hep.23032.
12. Keitel V, Reich M, Häussinger D. TGR5: pathogenetic role and/or therapeutic target in fibrosing cholangitis? Clin Rev Allergy Immunol. 2015;48:218-25. doi: 10.1007/s12016-014-8443-x.
13. Keitel V, Stindt J, Häussinger D. Bile acid-activated receptors: GPBAR1 (TGR5) and other G protein-coupled receptors. Handb Exp Pharmacol. 2019;256:19-49. doi: 10.1007/164_2019_230.
14. Klindt C , Reich M, Hellwig B, Stindt J, Rahnenführer J, Hengstler JG, et al. The G protein-coupled bile acid receptor TGR5 (Gpbar1) modulates endothelin-1 signaling in liver. Cells. 2019;8:E1467. doi:10.3390/cells8111467.
15. Maruyama T, Miyamoto Y, Nakamura T, Tamai Y, Okada H, Sugiyama E, et al. Identification of membrane-type receptor for bile acids (M-BAR). Biochem Biophys Res Commun. 2002;298:714-9.
16. Merlen G, Kahale N, Ursic-Bedoya J, Bidault-Jourdainne V, Simerabet H, Doignon I, et al. TGR5-dependent hepatoprotection through the regulation of biliary epithelium barrier function. Gut. 2020;69:146-57. doi: 10.1136/gutjnl-2018-316975.
17. Perino A, Pols TW, Nomura M, Stein S, Pellicciari R, Schoonjans K. TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation. J Clin Invest. 2014;124:5424-36. doi: 10.1172/JCI76289.
18. Perino A, Schoonjans K. TGR5 and immunometabolism: Insights from physiology and pharmacology. Trends Pharmacol Sci. 2015;36:847-57. doi: 10.1016/j.tips.2015.08.002.
19. Schenk A, Ghallab A, Hofmann U, Hassan R, Schwarz M, Schuppert A, et al. Physiologically-based modelling in mice suggests an aggravated loss of clearance capacity after toxic liver damage. Sci Rep. 2017;7:6224. doi: 10.1038/s41598-017-04574-z.
20. Svinka J, Pflügler S, Mair M, Marschall HU, Hengstler JG, Stiedl P, et al. Epidermal growth factor signaling protects from cholestatic liver injury and fibrosis. J Mol Med (Berl). 2017;95:109-17. doi: 10.1007/s00109-016-1462-8.
 
 
 

[*] Corresponding Author:

Ahmed Ghallab, Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt, eMail: ghallab@vet.svu.edu.eg