ABSTRACT
Hepatic fibrosis results from the accumulation of extracellular matrix-producing myofibroblasts in the liver. The mechanisms leading to the activation of hepatic stellate cells (HSCs) into myofibroblasts have been well described. By contrast, few molecular pathways leading to myofibroblast deactivation have been documented. Recently, the vitamin D-VDR axis has been shown to modulate HSC activity through a complex mechanism involving epigenetic modifications induced by the SMAD pathway.
Subject(s)
Gene Regulatory Networks , Liver/metabolism , Liver/pathology , Receptors, Calcitriol/metabolism , Signal Transduction , Animals , MaleABSTRACT
Epithelial-mesenchymal transition (EMT) is a physiological process occurring in the embryo. In adult organism, EMT could be involved in disease development. In the liver, the possibility that EMT of liver epithelial cells participate to liver fibrosis is increasingly discussed. Furthermore, the involvement of hepatocyte EMT to liver cancer biology has also been documented over the past few years. In this review, we will first describe how EMT participates to embryological development. We will then discuss the involvement of hepatocytes and biliary epithelial cells in liver fibrosis. Finally, we will describe how EMT may impact the metastatic process and resistance to therapy in hepatocellular carcinoma.
Subject(s)
Carcinoma, Hepatocellular/pathology , Epithelial-Mesenchymal Transition , Hepatocytes/pathology , Liver Cirrhosis/pathology , Liver Neoplasms/pathology , Carcinoma, Hepatocellular/genetics , Cell Dedifferentiation , Cell Differentiation , Disease Progression , Epithelial-Mesenchymal Transition/genetics , Humans , Liver Cirrhosis/genetics , Liver Neoplasms/genetics , Neoplasm InvasivenessABSTRACT
Whether bile acids regulate biliary epithelial cell (BEC) secretory functions in human is poorly known. The purpose of the study was to determine if human gallbladder-derived BEC exhibit bile acid transport activity that affect their secretory functions and to evaluate the influence of bile acid hydrophobicity in this response by comparing the effects of tauroursodeoxycholate (TUDC) and of taurochenodeoxycholate (TCDC). Expression of the apical sodium-dependent bile acid transporter (ASBT) and of the organic anion transporting polypeptide (OATP-A) was detected and associated with sodium-dependent and sodium-independent [(3)H]taurocholate uptake in BEC. Sodium-dependent uptake (K(m), 66 +/- 2.5 micromol/L; Vmax, 39.4 +/- 4.6 pmol/mg protein/min) was significantly higher than sodium-independent uptake. TCDC stimulated Cl(-) efflux and mucin secretion in cultured cells, and both effects were sodium-dependent. Both TCDC and TUDC were efficiently transported in BEC, as assessed by competitive uptake experiments. However, as compared with TCDC, TUDC induced significantly lower mucin secretion whereas there was no significant difference between TCDC- and TUDC-induced chloride efflux. Protein kinase C down-regulation caused a 70% reduction in TUDC-induced mucin secretion, but did not affect TCDC-induced secretion, which was mediated predominantly by Ca(2+)/calmodulin-dependent protein kinase II activation. These results provide evidence that bile acids may be transported mainly via ASBT in human gallbladder BEC and stimulate hydroelectrolytic and mucin secretion in these cells. Individual bile acids activate different signaling pathways leading to a different balance between mucin and chloride secretion. The differential effect of TUDC may cause a reduction in bile inspissation and provide a benefit in biliary disorders.
