The expression of ETAR in liver cirrhosis and liver cancer

Abstract

Endothelin receptors express differently in liver cirrhosis and liver cancer tissues and play a role in hepatic diseases by affecting HSCs and HSECs.

GPCRs and fibroblast heterogeneity in fibroblast‐associated diseases

“…Also, decreases the expression of IL-6 by BMM, preventing fibrosis [116,117] G-protein-coupled bile acid receptor 91 (GPR91) G i Succinate-induced activation leads to increased expression of α-SMA, TGF-β, and collagen I in HSCs [118] Neuropeptide Y receptor Y1 (Y1-R) G i Activation induces phosphorylation of mTOR, p70S6K, and 4EBP1 in HSCs leading to fibrosis [119] Lysophosphatidic acid receptor 1 (LPAR1) G i Enables activation and differentiation of HSCs into myofibroblast leading to actin rearrangement and proliferation while inhibiting HSC apoptosis [120] Smoothened receptor (SMO) G i Transduces the Hedgehog pathway resulting in EMT of the HSCderived myofibroblasts supporting their pro-fibrogenic phenotype [121] Frizzled receptor 2 (Fz2) G i Leads to the expression of collagen I and TGF-β leading to the differentiation of HSCs into myofibroblast [122] C5a receptor (C5aR) G i Activates HSCs to produce α-SMA, hyaluronic acid, and collagen IV while inhibiting apoptosis of TNF-α and ligand-induced HSC apoptosis [123] Apelin receptor G i Leads to the expression of pro-fibrotic genes like α-SMA and collagen I via the ERK signaling pathway [124] M2 acetylcholine receptor (M2) G i Induces HSC hyper-proliferation and upregulation of pro-fibrotic markers such as collagen I and TGF-β a [97] M3 acetylcholine receptor (M3) G q Agonist-mediated activation alleviates HSC activation, collagen deposition, pro-fibrotic and pro-ECM markers, diminishing liver injury a [98] Angiotensin II type 1 receptor (AT1R) G q Supports activation of HSCs and fibrosis via phosphorylation of JAK2 and following activation of RhoA/Rho-kinase [125] α1Aadrenoreceptor (ADRA1A) G q Expressed by activated HSCs, upregulates secretion of NF-κB, inducing pro-inflammatory phenotype, and increased HSC contraction [126] Serotonin receptor 1B (5-HT1B) G q Upregulated in activated HSCs requiring investigation into its specific role in fibrosis progression [127] Serotonin receptor 2A (5-HT2A) G q Antagonists decreased the activation of HSCs, expression of profibrotic markers, and inflammatory markers [128] Arginine vasopressin receptor 1A (AVPR1A) G q Induces increase in intracellular calcium and enhanced MAPK activity mediating HSC proliferation and contraction [129] Endothelin receptor type A (ETAR) G q Upregulated in activated HSCs expressing α-SMA. In-depth implications and associated signaling pathways need to be investigated [130] G protein-coupled receptor 55 (GPR55) G q Leads to the activation of acetyl-coenzyme A carboxylase initiating HSC activation [131] a Indicates GPCRs with both pro and anti-fibrotic effects in hepatic fibrosis.…”

Endothelins and liver cirrhosis

“…13 ET-1 acts by binding to endothelin A and/or B receptors, which are located on the membranes of endothelial cells and HSCs in the liver, and on other cell types, including vascular smooth muscle cells, Kupffer cells, polymorphonuclear cells, macrophages, and cells in the heart, brain, lungs, kidneys, and liver. 14,15 Platelet activating factors (PAF) in Kupffer cells and on membranes are increased 2-and 1.48-fold, respectively, in cirrhotic rats treated with by CCL4. Kupffer cells are the main reservoir of PAFs.…”

Endothelin receptors promote schistosomiasis-induced hepatic fibrosis via splenic B cells

“…Plasma ET-1 levels are increased in cirrhosis and correlate with the severity of liver disease and portal pressure [ 22 ]. Several studies by our and other groups have shown that elevated concentrations of ET-1 act on upregulated ETRs on hepatic stellate cells (HSCs) to cause increased contractility and intrahepatic sinusoidal resistance, resulting in portal hypertension [ 23 , 24 ]. The spleen plays a critical role in development of liver fibrosis and cirrhosis [ 25 ].…”