Molecular Regulation of Hepatic Fibrosis, an Integrated Cellular Response to Tissue Injury

Friedman, Scott L.

doi:10.1074/jbc.275.4.2247

Cited by 1,950 publications

(1,784 citation statements)

References 57 publications

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“…During fibrosis, the components and quantity of ECM will change and type I and III collagen will increase significantly. Fibril-forming ECM also accelerates HSCs activation through interaction with integrins, the classic ECM receptors, and binding to at least one tyrosine kinase receptor (RTK) [16]. Our present data showed that hypoxia increased the protein expression of collagen type I (Fig.…”

Section: Discussionsupporting

confidence: 59%

Hypoxia induces the activation of human hepatic stellate cells LX‐2 through TGF‐β signaling pathway

et al. 2006

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Hypoxia is a common environmental stress factor and is also associated with various physiological and pathological conditions such as fibrogenesis. The activation of hepatic stellate cells (HSCs) is the key event in the liver fibrogenesis. In this study, the behavior of human HSCs LX-2 in low oxygen tension (1% O 2 ) was analyzed. Upon hypoxia, the expression of HIF-1a and VEGF gene was induced. The result of Western blotting showed that the expression of a-SMA was increased by hypoxic stimulation. Furthermore, the expression of MMP-2 and TIMP-1 genes was increased. Hypoxia also elevated the protein expression of the collagen type I in LX-2 cells. The analysis of TGF-b/ Smad signaling pathway showed that hypoxia potentiated the expression of TGF-b1 and the phosphorylation status of Smad2. Gene expression profiles of LX-2 cells induced by hypoxia were obtained by using cDNA microarray technique.

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Section: Discussionsupporting

confidence: 59%

Hypoxia induces the activation of human hepatic stellate cells LX‐2 through TGF‐β signaling pathway

et al. 2006

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“…These cells, when activated, produce and secrete cytokines; cytokines may be proinflammatory, such as TNF-a and IL-1, or profibrotic, such as TGF-b. These proteins can further increase ROS and play important roles in the mediation of hepatic injury [23,[85][86][87], such as fatty liver, by inhibiting lipase of lipoprotein and adiponectin and fibrosis as a result of HSC activation [88][89][90].…”

Section: Viral Hepatitis and Free Radicalsmentioning

confidence: 99%

Role of free radicals in liver diseases

2009

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Reactive oxygen and nitrogen species (ROS and RNS) are produced by metabolism of normal cells. However, in liver diseases, redox is increased thereby damaging the hepatic tissue; the capability of ethanol to increase both ROS/RNS and peroxidation of lipids, DNA, and proteins was demonstrated in a variety of systems, cells, and species, including humans. ROS/RNS can activate hepatic stellate cells, which are characterized by the enhanced production of extracellular matrix and accelerated proliferation. Cross-talk between parenchymal and nonparenchymal cells is one of the most important events in liver injury and fibrogenesis; ROS play an important role in fibrogenesis throughout increasing platelet-derived growth factor. Most hepatocellular carcinomas occur in cirrhotic livers, and the common mechanism for hepatocarcinogenesis is chronic inflammation associated with severe oxidative stress; other risk factors are dietary aflatoxin B 1 consumption, cigarette smoking, and heavy drinking. Ischemia-reperfusion injury affects directly on hepatocyte viability, particularly during transplantation and hepatic surgery; ischemia activates Kupffer cells which are the main source of ROS during the reperfusion period. The toxic action mechanism of paracetamol is focused on metabolic activation of the drug, depletion of glutathione, and covalent binding of the reactive metabolite N-acetyl-pbenzoquinone imine to cellular proteins as the main cause of hepatic cell death; intracellular steps critical for cell death include mitochondrial dysfunction and, importantly, the formation of ROS and peroxynitrite. Infection with hepatitis C is associated with increased levels of ROS/RNS and decreased antioxidant levels. As a consequence, antioxidants have been proposed as an adjunct therapy for various liver diseases.

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“…Increased cell adhesion to collagen and reduced cell motility may be a necessary mechanism to compensate for the loss of cell-cell contact, which is typically observed in damaged hepatocytes at the portalparenchymal interface. 41 The MMP data suggest a role for DDR1 in regulation of extracellular MMP1 and MMP2 in hepatocytes, and this role was independent of the three mutated tyrosines of DDR1. However, the overall effect of increased MMP2 and decreased MMP1 after prolonged collagen exposure might not have significantly influenced the apparent dominant effect of collagen adhesion under the assay conditions.…”

Section: Ddr1 In Human Livermentioning

confidence: 89%

“…In cirrhotic human liver, hepatocytes at the portal-parenchymal interface are often swollen and lack polarity. 41 Loss of cell polarity on some hepatocytes in cirrhotic liver, in particular those at the portal-parenchymal interface, seemed to result in unpolarized trafficking of DDR1, as also occurs with the apical marker dipeptidyl peptidase IV. 42 Both DDR1 and dipeptidyl peptidase IV bind to ECM components, which emphasizes the importance of this function for hepatocytes.…”

Section: Ddr1 In Human Livermentioning

confidence: 99%

Discoidin Domain Receptor 1

Song

Shackel

Wang

et al. 2011

The American Journal of Pathology

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Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds and is activated by collagens. Transcriptional profiling of cirrhosis in human liver using a DNA array and quantitative PCR detected elevated mRNA expression of DDR1 compared with that in nondiseased liver. The present study characterized DDR1 expression in cirrhotic and nondiseased human liver and examined the cellular effects of DDR1 expression. mRNA expression of all five isoforms of DDR1 was detected in human liver, whereas DDR1a demonstrated differential expression in liver with hepatitis C virus and primary biliary cirrhosis compared with nondiseased liver. In addition, immunoblot analysis detected shed fragments of DDR1 more readily in cirrhotic liver than in nondiseased liver. Inasmuch as DDR1 is subject to protease-mediated cleavage after prolonged interaction with collagen, this differential expression may indicate more intense activation of DDR1 protein in cirrhotic compared with nondiseased liver. In situ hybridization and immunofluorescence localized intense DDR1 mRNA and protein expression to epithelial cells including hepatocytes at the portal-parenchymal interface and the luminal aspect of the biliary epithelium. Overexpression of DDR1a altered hepatocyte behavior including increased adhesion and less migration on extracelular matrix substrates. DDR1a regulated extracellular expression of matrix metalloproteinases 1 and 2. These data elucidate DDR1 function pertinent to cirrhosis and indicate the importance of epithelial cell-collagen interactions in chronic liver injury.

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Molecular Regulation of Hepatic Fibrosis, an Integrated Cellular Response to Tissue Injury

Cited by 1,950 publications

References 57 publications

Hypoxia induces the activation of human hepatic stellate cells LX‐2 through TGF‐β signaling pathway

Hypoxia induces the activation of human hepatic stellate cells LX‐2 through TGF‐β signaling pathway

Role of free radicals in liver diseases

Discoidin Domain Receptor 1

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