Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0239946 (liver fibrosis)
 8,268 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liver cirrhosis is characterized by hepatic dysfunction with extensive accumulation of fibrous tissue in the liver. In response to chronic hepatic injury, hepatic portal myofibroblasts and activated hepatic stellate cells (HSCs) play a role in liver fibrosis. Although administration or gene expression of hepatocyte growth factor (HGF) leads to improvement in hepatic fibrosis/cirrhosis, the related mechanisms are not fully understood. We investigated mechanisms involved in resolution from liver cirrhosis by HGF, focusing on growth regulation and apoptosis in portal myofibroblasts. Cultured rat HSCs could not proliferate, were withdrawn after passage, and were replaced by proliferating portal myofibroblasts during the passages. In quiescent HSCs, c-Met receptor expression was undetected whereas c-Met receptor expression was detected in activated HSCs and liver myofibroblasts expressing alpha-smooth muscle actin (alpha-SMA), suggesting that activated HSCs and portal myofibroblasts are targets of HGF. For cultured rat portal myofibroblasts, HGF counteracted phosphorylation of extracellular signal-regulated kinase (Erk) 1/2 and mitogenic stimulus induced by platelet-derived growth factor, induced c-jun N-terminal kinase (JNK) 1 phosphorylation, and promoted apoptotic cell death. In the dimethylnitrosamine rat model of liver cirrhosis, administration of HGF suppressed proliferation while promoting apoptosis of alpha-SMA-positive cells in the liver, events that were associated with reduced hepatic expressions of alpha-SMA and histological resolution from liver cirrhosis. Growth inhibition and enhanced apoptosis in portal myofibroblasts by HGF are newly identified mechanisms aiding resolution from liver fibrosis/cirrhosis by HGF.
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PMID:Growth inhibition and apoptosis in liver myofibroblasts promoted by hepatocyte growth factor leads to resolution from liver cirrhosis. 1579 83

Tissue TG (transglutaminase) or TG2 is the most ubiquitously expressed member of the large TG family that catalyses deamidation of a glutamine residue, formation of an N epsilon(gamma-glutamyl)-lysine cross-linking between lysine and glutamine residues and/or covalent incorporation of polyamines into a glutamine residue, exerting a number of physiological and/or pathological functions. Extracellular TG2 contributes to wound healing and exacerbation of liver fibrosis through a role in extracellular matrix assembly and cell adhesion. Intracellular TG2 acts as a GTPase in normal cells when the intracellular Ca2+ concentration is as low as 10-20 nM, participating in the transmembrane signalling of phospholipase C delta as a component of alpha1-adrenergic receptor complexes, and thereby supporting the growth of hepatic cells. When cells are injured and the intracellular Ca2+ concentration rises to more than 700-800 nM, TG2 dramatically alters its structure and transforms into a cross-linking enzyme. TG2 primarily exists in the cytosol in normal cells, but is distributed among multiple intracellular milieus during tissue injury or apoptosis. In particular, TG2 has been shown to be abundant in the nuclei of cells undergoing apoptosis, although its role in the nucleus and the underlying mechanisms remain unresolved. Recently, three findings in the study of alcoholic steatohepatitis have shed light on these issues. Omary's group disclosed that TG2-mediated cross-linking of keratin 8 is essential for the formation of Mallory-Denk bodies. We have demonstrated that in both mouse models of alcoholic steatohepatitis and human patients with alcoholic steatohepatitis, TG2 translocates into the nucleus and provokes hepatocyte death via cross-linking and inactivation of a transcription factor, Sp1, leading to down-regulation of the hepatocyte growth factor receptor, c-Met. Furthermore, Giebeler et al. has reported that down-regulation of c-Met is associated with liver fibrosis. In the present review article, we introduce these recent advances in knowledge with regard to the the roles of TG2 in alcoholic steatohepatitis.
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PMID:Recent advances in understanding the roles of transglutaminase 2 in alcoholic steatohepatitis. 2019 18

HGF/c-Met signaling plays a pivotal role in hepatocyte survival and tissue remodeling during liver regeneration. HGF treatment accelerates resolution of fibrosis in experimental animal models. Here, we utilized Met(fl/fl);Alb-Cre(+/-) conditional knockout mice and a carbon tetrachloride(CCl(4))-induced liver fibrosis model to formally address the role of c-Met signaling in hepatocytes in the context of chronic tissue injury. Histological changes during injury (4weeks) and healing phase (4weeks) were monitored by immunohistochemistry; expression levels of selected key fibrotic molecules were evaluated by western blotting, and time-dependent global transcriptomic changes were examined using a microarray platform. Loss of hepatocyte c-Met signaling altered hepatic microenvironment and aggravated hepatic fibrogenesis. Greater liver damage was associated with decreased hepatocyte proliferation, excessive stellate cell activation and rapid dystrophic calcification of necrotic areas. Global transcriptome analysis revealed a broad impact of c-Met on critical signaling pathways associated with fibrosis. Loss of hepatocyte c-Met caused a strong deregulation of chemotactic and inflammatory signaling (MCP-1, RANTES, Cxcl10) in addition to modulation of genes involved in reorganization of the cytoskeletal network (Actb, Tuba1a, Tuba8), intercellular communications and adhesion (Adam8, Icam1, Itgb2), control of cell proliferation (Ccng2, Csnk2a, Cdc6, cdk10), DNA damage and stress response (Rad9, Rad52, Ercc4, Gsta1 and 2, Jun). Our study demonstrates that deletion of c-Met receptor in hepatocytes results in pronounced changes in hepatic metabolism and microenvironment, and establishes an essential role for c-Met in maintaining the structural integrity and adaptive plasticity of the liver under adverse conditions.
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PMID:Loss of c-Met accelerates development of liver fibrosis in response to CCl(4) exposure through deregulation of multiple molecular pathways. 2238 77