Interestingly, hepatic content of and were measured by qPCR. Our data have identified a mechanism of -3 PUFAs in ameliorating liver fibrosis. As one of the most common consequences R-BC154 of chronic liver diseases, liver fibrosis represents a significant world-wide health problem. It can be classified as a wound-healing response to chronic hepatic injury, which may be caused by alcohol abuse, hepatitis virus infection, autoimmune disorders, biliary obstruction or nonalcoholic steatohepatitis, and is characterized by excessive scar formation due to overproduction and deposition of extracellular matrix (ECM) components resulted from an imbalance of ECM molecule metabolism either by an increased synthesis or decreased degradation of ECM components or both1,2,3. Activation of hepatic R-BC154 stellate cells (HSCs), a major cell type responsible for increased synthesis of ECM proteins, represents a crucial event in the pathogenic sequence of fibrosis and thus provides an important framework to define potential strategies for anti-fibrotic therapy. Like liver sinusoidal endothelial cells and Kupffer cells, quiescent HSCs are non-parenchymal cells. They R-BC154 normally reside in the space of Disse, containing bunches of vitamin A-riching lipid droplets, while activated HSCs lose cytoplasmic lipid droplets and trans-differentiate to proliferative, fibrogenicmyofibroblasts, and are characterized by the over-expression of -SMA1,2,3,4. Fish oil supplementation, usually containing a mix of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as major constituents, has been reported to be generally beneficial in the onset and progression of several chronic diseases, including coronary artery disease and atherosclerosis, diabetes and cancer5,6,7,8,9,10. Recently, there has been growing interest in -3 PUFAs supplementation as potential treatment for liver diseases11,12,13,14. However, there is little information regarding the impact of -3 PUFAs on the progression of liver fibrosis. Interestingly, EPA and DHA exert a potent anti-oxidative stress and anti-inflammatory activity in various cell lines, suggesting that -3 PUFAs R-BC154 may have an anti-fibrotic effect on the liver. Elevated levels of the transcriptional regulators Yes-associated protein (YAP) and transcriptional coactivators with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, are associated with a broad range of aggressive cancers including hepatocellular carcinoma15,16,17. Moreover, YAP/TAZ has also been shown to play an essential role in controlling liver cell fate and regulating liver response to cholestasis18. In addition, a large body of data has accumulated showing that CTGF, the most highly characterized YAP target gene19, is over-expressed in fibrotic liver and activated HSCs. CTGF induces the synthesis and secretion of ECM proteins, notably of fibrillar collagens which are a major component of fibrous deposits20,21,22,23,24. On the other hand, transforming growth factor- (TGF-) has been considered the most important factor that drives liver fibrosis. Suppression of TGF- expression or its downstream signaling pathway can ameliorate or even prevent liver fibrosis25. Interestingly, it has been reported that YAP/TAZ, interact with TGF–induced SMAD2/3 in the nucleus, suggesting that YAP/TAZTEADSMAD2/3 complexes coordinately regulate TGF–induced transcriptional program16,26. Furthermore, studies have shown that Notch signaling participates in the progression of fibrosis and can directly up-regulate Col11 and Col12 promoter activity through a Hes1-dependent mechanism27. More recently, the Notch pathway, including Notch1/2, Jag1 and the Notch target genes Hes1 and Sox9 have also been shown to be directly targeted by the YAP/TEAD complex18. Similarly, it has also been reported that YAP/TAZ functions as a regulator of microprocessor activity and regulates biogenesis of miRNA28,29,30, some R-BC154 of which play an important role in liver fibrosis. Moreover, recent study has shown that YAP drives the earliest changes in gene expression during hepatic stellate cell activation31. Elevated YAP/TAZ expression correlates with bile duct proliferation and fibrosis15,32,33. Connecting these previously reported phenomena, we focused on the transcriptional effectors YAP/TAZ as a potential regulator of liver fibrosis. In this study, we demonstrate for the first time that -3 Mouse monoclonal to KLHL11 PUFAs attenuate CCl4-induced liver fibrosis and inhibit hepatic stellate cell proliferation and activation. Our findings indicate that the expression of YAP and TAZ are up-regulated in CCl4-induced liver fibrosis. Furthermore, -3 PUFAs inhibit hepatic stellate cell lines proliferation and activation by promoting.