Regulation of hepatic stellate cell proliferation and collagen synthesis by proteinase-activated receptors

Gaça, Marianna; Zhou, Xiaoying; Benyon, R. Christopher

doi:10.1016/s0168-8278(01)00285-9

Cited by 123 publications

(116 citation statements)

References 43 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…Thrombin activation of PAR-1 has been shown to drive multiple NAFLD-associated pathologies, including hepatic lipid accumulation, inflammation and hepatocellular injury, depending on the experimental setting (Kassel et al, , 2012Kopec et al, 2014;Luyendyk et al, 2010). Notably, PAR-1 activation promotes stellate cell activation in vitro (Fiorucci et al, 2004;Gaca et al, 2002), and hepatic fibrosis is reduced in PAR-1 À/À mice challenged chronically with hepatocellular or biliary toxicants . Collectively, these studies indicate a central role for coagulation and thrombin signaling across the spectrum of NAFLD/NASH pathologies.…”

mentioning

confidence: 99%

From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis

et al. 2016

View full text Add to dashboard Cite

Emerging evidence supports a role for environmental chemical exposure in the pathology of non-alcoholic fatty liver disease (NAFLD), a disease process tightly linked to increased activity of the blood coagulation cascade. Exposure of C57BL/6 mice to the persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) recapitulates features of the NAFLD spectrum, including steatosis, hepatic injury, inflammation, and fibrosis. We assessed coagulation cascade activation, and determined the role of the thrombin receptor protease activated receptor-1 (PAR-1) in experimental TCDDelicited NAFLD. Chronic exposure to TCDD (30 mg/kg every 4 days for 28 days) was associated with intrahepatic coagulation, indicated by increased plasma thrombin-antithrombin levels and hepatic fibrin(ogen) deposition. PAR-1 deficiency diminished TCDD-elicited body weight loss and relative liver weight was reduced in TCDD-exposed PAR-1 À/À mice compared with TCDD-exposed wild-type mice. PAR-1 deficiency did not affect TCDD-induced hepatic steatosis or hepatocellular injury, as indicated by serum alanine aminotransferase activity. Despite a lack of effect on these 2 features of NAFLD pathology, PAR-1 deficiency was associated with a reduction in hepatic inflammation evident in liver histopathology, and reflected by a reduction in serum levels of the proinflammatory cytokine interleukin-6. Moreover, TCDD-driven hepatic collagen deposition was markedly reduced in PAR-1-deficient mice. These results indicate that experimental TCDD-elicited steatohepatitis is associated with coagulation cascade activation and PAR-1-driven hepatic inflammation and fibrosis.

show abstract

mentioning

confidence: 99%

From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Thus we (34) and others (27) have shown that PAR-1 was overexpressed in human liver fibrosis. In vitro, thrombin via PAR-1 stimulates rat (16,26) and human (24) hepatic stellate cell proliferation; it regulates their migration (18) and their capacity to synthesize extracellular matrix components (17) and protease inhibitors (30). Finally, we recently demonstrated (15) that a thrombin antagonist was protective against carbon tetrachloride (CCl 4 )-induced fibrosis.…”

mentioning

confidence: 99%

“…Activation of hemostasis would result in the occurrence of fibrin deposition and microthrombi in the liver parenchyma (31), leading to hypoxia and subsequent fibrogenesis (10,37). However, PAR-1 signaling is known to result in the increased expression of a series of extracellular matrix molecules (7,17) and profibrogenic mediators such as connective tissue growth factor (CTGF) (8) or monocyte chemotactic protein (MCP)-1 (26) and could thus account for the profibrogenic effect of thrombin. Fiorucci et al (16) showed that a PAR-1 antagonist reduced liver fibrosis induced by bile duct ligation.…”

mentioning

confidence: 99%

Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis

Rullier

Gillibert-Duplantier²,

Costet³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Thrombin inhibition protects against liver fibrosis. However, it is not known whether the thrombin profibrogenic effect is due to effects on blood coagulation or to signaling via protease-activated receptors (PARs). We took advantage of the lack of blood coagulation defects in PAR-1-knockout mice. Acute carbon tetrachloride (CCl4) toxicity was similar in wild-type (WT), PAR-1−/−, and PAR-1+/−mice as judged by aminotransferase levels, area of liver necrosis, and liver peroxidation measured by Fourier-transformed infrared spectroscopy. Fifteen mice/group received CCl4or its solvent for 6 wk (300 μl/kg, 3 times a week). Fibrosis area was increased 10-fold by CCl4treatment in WT mice. PAR-1 deficiency protected against fibrosis, with 36% and 56% decrease in PAR-1+/−and PAR-1−/−mice, respectively ( P < 0.001). Similar results were obtained for area of activated fibrogenic cells (64% and 79% decrease in PAR-1+/−and PAR-1−/−mice, respectively, P < 0.001). These findings were corroborated by measurements of type I collagen, matrix metalloproteinase-2, and PDGF-β receptor mRNA levels. There was also a significant decrease in T lymphocyte infiltration in PAR-1-deficient mice. Altogether, these results suggest that thrombin profibrogenic effects are independent of effects on blood coagulation and are instead due to direct effects on fibrogenic cells and possibly on T lymphocytes.

show abstract

“…Thrombin can also activate signal transduction pathways in cells by activating protease-activated receptor-1 (PAR-1) [15]. This receptor is expressed on HSCs, and studies have shown that HSCs proliferate in vitro when treated with thrombin, an effect that was prevented in HSCs from PAR-1 knockout mice [16]. In addition, liver fibrosis is reduced in PAR-1 knockout mice and in mice treated with a PAR-1 antagonist [17,18].…”

Section: Mediators That Stimulate Hsc Proliferationmentioning

confidence: 99%

Phenotypic Changes in Hepatic Stellate Cells in Response to Toxic Liver Injury

Copple

2014

Curr Pathobiol Rep

View full text Add to dashboard Cite

Hepatic stellate cells (HSCs) are the main extracellular matrix-producing cell type in the liver. These cells exist in a quiescent state in normal liver and an activated state in damaged liver. During quiescence, HSCs store and release various retinoids. After injury to the liver, however, various protein and non-protein mediators are released from cells that stimulate HSCs to differentiate into myofibroblasts, a process termed activation. Activated HSCs begin to express a-smooth muscle actin and migrate to sites of injury through chemotaxis. Within the damaged region of liver, these cells become contractile and produce growth factors that promote hepatocyte replication and angiogenesis, produce extracellular matrix that forms the scaffold for liver repair, and produce proteins that modulate immune cell function. Once liver repair is complete and liver function is restored, HSCs revert back to a quiescent phenotype or die by apoptosis. If liver injury becomes chronic, however, these processes persist resulting in the formation of an extensive scar (i.e., fibrosis) that ultimately leads to liver failure. Because of the importance of these cells to the development of liver fibrosis, there has been extensive research into understanding the mechanisms that drive HSC activation after injury and the mechanisms that regulate reversion of these cells back to quiescence after resolution of injury. In addition, there has been great interest in identifying the various functions of HSCs after acute and chronic injury. The aim of this review is to briefly discuss the phenotypic changes that occur in HSCs after acute and chronic liver injury and to highlight some of the important functions of these cells during repair of the liver.

show abstract

Regulation of hepatic stellate cell proliferation and collagen synthesis by proteinase-activated receptors

Cited by 123 publications

References 43 publications

From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis

From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis

Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis

Phenotypic Changes in Hepatic Stellate Cells in Response to Toxic Liver Injury

Contact Info

Product

Resources

About