Despite the initial belief that non-alcoholic fatty liver disease is a benign disorder, it is now recognized that fibrosis progression occurs in a significant number of patients. Furthermore, hepatic steatosis has bee...Despite the initial belief that non-alcoholic fatty liver disease is a benign disorder, it is now recognized that fibrosis progression occurs in a significant number of patients. Furthermore, hepatic steatosis has been identified as a risk factor for the progression of hepatic fibrosis in a wide range of other liver diseases. Here, we established an in vitro model to study the effect of hepatic lipid accumulation on hepatic stellate cells （HSCs）, the central mediators of liver fibrogenesis. Primary human hepatocytes were incubated with the saturated fatty acid palmitate to induce intracellular lipid accumulation. Subsequently, human HSCs were incubated with conditioned media （CM） from steatotic or control hepatocytes. Lipid accumulation in hepatocytes induced the release of factors that accelerated the activation and proliferation of HSC, and enhanced their resistance to apoptosis, largely mediated via activation of the PI-3-kinase pathway. Furthermore, CM from steatotic hepatocytes induced the expression of the profibrogenic genes TGF-β, tissue inhibitor of metallo-proteinase-1 （TIMP-1）, TIMP-2 and matrix-metallo-proteinase-2, as well as nuclear-factor κB-dependent MCP-1 expression in HSC. In summary, our in vitro data indicate a potential mechanism for the pathophysiological link between hepatic steatosis and fibrogenesis in vivo. Herewith, this study provides an attractive in vitro model to study the molecular mechanisms of steatosis-induced fibrogenesis, and to identify and test novel targets for antifibrotic therapies in fatty liver disease.展开更多
Atrial fibrosis is common in atrial fibrillation （AF）. Experimental studies have provided convincing evidence that fibrotic transformation of atrial myocardium results in deterioration of atrial conduction, increasi...Atrial fibrosis is common in atrial fibrillation （AF）. Experimental studies have provided convincing evidence that fibrotic transformation of atrial myocardium results in deterioration of atrial conduction, increasing anisotropy of impulse propagation and building of boundaries that promote re-entry in the atrial walls that maybe directly relevant for the mechanisms responsible for maintaining AF. Whether or not fibrosis is a result of structural remodelling caused by persistent AF or a manifestation of occult myocardial process that leads to development of arrhythmia is less clear. Human data indicate the presence of association between persistency of AF and the extent of structural changes in atrial myocardium. The role atrial fibrosis plays in the mechanisms of AF, however, may differ between patients with structurally normal hearts, such as lone AF, and those with advanced cardiovascular comorbidities.展开更多
Advances in clinical and fimdamental research, which have been promoted over last decades have led to a well- established understanding of atrial fibrillation （AF） as an epiphenomenon that despite similar manifestat...Advances in clinical and fimdamental research, which have been promoted over last decades have led to a well- established understanding of atrial fibrillation （AF） as an epiphenomenon that despite similar manifestations may have different underlying mechanisms and thus require in- dividualized treatments. With rare exceptions of AF caused by mutations in genes coding ion channels in pa- tients with structurally normal atria, fibrotic replacement of atrial myocardium remains the comer stone of atrial pa- thology in patients with AF.展开更多
文摘Despite the initial belief that non-alcoholic fatty liver disease is a benign disorder, it is now recognized that fibrosis progression occurs in a significant number of patients. Furthermore, hepatic steatosis has been identified as a risk factor for the progression of hepatic fibrosis in a wide range of other liver diseases. Here, we established an in vitro model to study the effect of hepatic lipid accumulation on hepatic stellate cells （HSCs）, the central mediators of liver fibrogenesis. Primary human hepatocytes were incubated with the saturated fatty acid palmitate to induce intracellular lipid accumulation. Subsequently, human HSCs were incubated with conditioned media （CM） from steatotic or control hepatocytes. Lipid accumulation in hepatocytes induced the release of factors that accelerated the activation and proliferation of HSC, and enhanced their resistance to apoptosis, largely mediated via activation of the PI-3-kinase pathway. Furthermore, CM from steatotic hepatocytes induced the expression of the profibrogenic genes TGF-β, tissue inhibitor of metallo-proteinase-1 （TIMP-1）, TIMP-2 and matrix-metallo-proteinase-2, as well as nuclear-factor κB-dependent MCP-1 expression in HSC. In summary, our in vitro data indicate a potential mechanism for the pathophysiological link between hepatic steatosis and fibrogenesis in vivo. Herewith, this study provides an attractive in vitro model to study the molecular mechanisms of steatosis-induced fibrogenesis, and to identify and test novel targets for antifibrotic therapies in fatty liver disease.
文摘Atrial fibrosis is common in atrial fibrillation （AF）. Experimental studies have provided convincing evidence that fibrotic transformation of atrial myocardium results in deterioration of atrial conduction, increasing anisotropy of impulse propagation and building of boundaries that promote re-entry in the atrial walls that maybe directly relevant for the mechanisms responsible for maintaining AF. Whether or not fibrosis is a result of structural remodelling caused by persistent AF or a manifestation of occult myocardial process that leads to development of arrhythmia is less clear. Human data indicate the presence of association between persistency of AF and the extent of structural changes in atrial myocardium. The role atrial fibrosis plays in the mechanisms of AF, however, may differ between patients with structurally normal hearts, such as lone AF, and those with advanced cardiovascular comorbidities.
文摘Advances in clinical and fimdamental research, which have been promoted over last decades have led to a well- established understanding of atrial fibrillation （AF） as an epiphenomenon that despite similar manifestations may have different underlying mechanisms and thus require in- dividualized treatments. With rare exceptions of AF caused by mutations in genes coding ion channels in pa- tients with structurally normal atria, fibrotic replacement of atrial myocardium remains the comer stone of atrial pa- thology in patients with AF.
