These GW4064-treated cells also showed reduced contractile response to ET-1 in comparison to untreated HSCs. We have further shown that GW4064 treatment inhibited the ET-1-mediated contraction in fully activated HSCs. Our studies unveiled a new mechanism that might contribute to the anti-cirrhotic effects of FXR ligands. We have confirmed and expanded previous reports that activation of FXR in HSCs inhibits their transdifferentiation. We have also shown for the first time that FXR ligands exert inhibitory effect on their contractile response to ET-1, a potent vasoconstrictor. It has been well established that activation of HSCs plays a key role in the development of cirrhosis. Activation of HSCs is associated with altered and increased production of ECM that contributes significantly to the fibrotic changes in the chronic liver injury. Increasing evidence also suggests that activated HSCs gains contractile function, which contributes to the intrahepatic hemodynamic changes in cirrhosis. HSCs reside in the perisinusoidal space and extend elongate protrusions that run along and encircle one or more sinusoids. Activated stellate cells express a-smooth muscle actin, a marker of nonmuscle cell contractility, in patients with different types of chronic liver injury. A number of studies have demonstrated HSC contractile response following stimulation by many different vasoactive mediators including ET-1, arginine vasopressin, angiotensin II, thrombin, eicosanoids, and a1-adrenergic agonists. The best- studied and most potent agonist for stellate cell contraction is ET- 1. ET-1 was originally identified as a potent vasoconstrictor produced mainly by endothelial cells. During liver injury activated stellate cells become a major source of ET-1. Stellate cells also express endothelin receptors and ET-1 has a prominent contractile effect on stellate cells and myofibroblasts, which may contribute to portal hypertension in the cirrhotic liver. In addition, ET-1 promotes the proliferation of early-cultured stellate cells, whereas it inhibits fully activated ones. Thus, ET-1 exhibits an autocrine effect on HSC and is involved in both HSC activation and their contractile response. For example, if a polymorphism delays leader peptide cleavage, it might slow processivity through the endoplasmic reticulum, increasing steady-state levels of envelope. A second explanation for the differences in magnitudes observed in our assays may have to do with the nature of the reporter protein used in these studies.CL1-deficient mice lack the epidermal barrier, while CL5-deficient mice lack the blood-brain barrier, indicating that the regulation of the TJ barrier by modulation of CLs may be a promising method for drug delivery. Clostridium perfringens enterotoxin causes food poisoning in humans. An interaction between the C-terminal domain of CPE with CL4 deregulates the TJ barrier.