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• W2545089922 abstract "Nonalcoholic steatohepatitis leads to cirrhosis and cancer in a rising number of patients with metabolic syndrome. In this issue of Cell Metabolism, Wang et al., 2016Wang Z. Zheng Z. Caviglia J.M. Corey K.E. Herfel T.M. Masia R. Chung R. Lefkowitch J.H. Schwabe R.F. Tabas I. Cell Metab. 2016; 24 (this issue): 848-862Abstract Full Text Full Text PDF Scopus (203) Google Scholar identify the transcriptional co-activator Taz as a driver of inflammation and fibrosis through the induction of Indian hedgehog in hepatocytes, which stimulates fibrogenesis by hepatic stellate cells. Nonalcoholic steatohepatitis leads to cirrhosis and cancer in a rising number of patients with metabolic syndrome. In this issue of Cell Metabolism, Wang et al., 2016Wang Z. Zheng Z. Caviglia J.M. Corey K.E. Herfel T.M. Masia R. Chung R. Lefkowitch J.H. Schwabe R.F. Tabas I. Cell Metab. 2016; 24 (this issue): 848-862Abstract Full Text Full Text PDF Scopus (203) Google Scholar identify the transcriptional co-activator Taz as a driver of inflammation and fibrosis through the induction of Indian hedgehog in hepatocytes, which stimulates fibrogenesis by hepatic stellate cells. The epidemic of non-alcoholic steatohepatitis (NASH) associated with obesity and the metabolic syndrome is surfacing as the most common cause of chronic liver disease throughout the world (Younossi et al., 2016Younossi Z.M. Koenig A.B. Abdelatif D. Fazel Y. Henry L. Wymer M. Hepatology. 2016; 64: 73-84Crossref PubMed Scopus (5279) Google Scholar) and will become the largest indication for liver transplantation in the US by 2020. Characterized by portal inflammation, steatosis, and a specialized form of hepatocyte injury called ballooning, the disease leads to progressive fibrosis and ultimately cirrhosis, with a heightened risk of primary liver cancer (Satapathy and Sanyal, 2015Satapathy S.K. Sanyal A.J. Semin. Liver Dis. 2015; 35: 221-235Crossref Scopus (246) Google Scholar). Despite the recognition of its public health impact, we lack an integrated hierarchy of pathogenic events underlying this illness, which is a critical requirement for optimizing its treatment. The study in this issue of Cell Metabolism by Wang et al., 2016Wang Z. Zheng Z. Caviglia J.M. Corey K.E. Herfel T.M. Masia R. Chung R. Lefkowitch J.H. Schwabe R.F. Tabas I. Cell Metab. 2016; 24 (this issue): 848-862Abstract Full Text Full Text PDF Scopus (203) Google Scholar introduces an important new mechanistic element to our understanding by demonstrating a substantive role for the transcriptional co-activator Taz in hepatocytes in several NASH animal models with corroborating evidence in human NASH (Wang et al., 2016Wang Z. Zheng Z. Caviglia J.M. Corey K.E. Herfel T.M. Masia R. Chung R. Lefkowitch J.H. Schwabe R.F. Tabas I. Cell Metab. 2016; 24 (this issue): 848-862Abstract Full Text Full Text PDF Scopus (203) Google Scholar). Taz, also known as WWTR1 (transcriptional coactivator with PDZ-binding motif), is an important downstream element of the hippo core kinase cascade, which was first uncovered in Drosophila. Together with its orthologous coactivator Yap (Yes-associated protein), the proteins exhibit a de-phosphorylation-dependent translocation to the nucleus, where they regulate transcription by interacting with the TEA domain (TEAD) to activate specific target genes. Most studies in liver to date have implicated Yap, but not Taz, in liver size regulation, regeneration, stem cell renewal, and tumorigenesis (Yimlamai et al., 2015Yimlamai D. Fowl B.H. Camargo F.D. J. Hepatol. 2015; 63: 1491-1501Abstract Full Text Full Text PDF Scopus (133) Google Scholar). More recently, however, both Yap and Taz have been identified as regulators of metabolism and nutrient-sensing (Santinon et al., 2016Santinon G. Pocaterra A. Dupont S. Trends Cell Biol. 2016; 26: 289-299Abstract Full Text Full Text PDF Scopus (115) Google Scholar), but only a single report has ascribed to Yap a role in NASH (Machado et al., 2015Machado M.V. Michelotti G.A. Pereira T.A. Xie G. Premont R. Cortez-Pinto H. Diehl A.M. J. Hepatol. 2015; 63: 962-970Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). Wang et al., 2016Wang Z. Zheng Z. Caviglia J.M. Corey K.E. Herfel T.M. Masia R. Chung R. Lefkowitch J.H. Schwabe R.F. Tabas I. Cell Metab. 2016; 24 (this issue): 848-862Abstract Full Text Full Text PDF Scopus (203) Google Scholar have explored the role of Taz within hepatocytes in three murine models of fatty liver disease and contrast its behavior to a toxic model of liver injury and fibrosis due to carbon tetrachloride (CCl4). The development and validation of rodent models of NASH remains an important unmet need, and Wang et al., 2016Wang Z. Zheng Z. Caviglia J.M. Corey K.E. Herfel T.M. Masia R. Chung R. Lefkowitch J.H. Schwabe R.F. Tabas I. Cell Metab. 2016; 24 (this issue): 848-862Abstract Full Text Full Text PDF Scopus (203) Google Scholar sought to replicate key features of the human disease. In these models, as well as in human tissues, there was marked elevation of Taz expression. These models appear faithful to human NASH both histologically and metabolically and could be more comprehensively compared to human tissues in future studies using genomic methods, as recently reported (Teufel et al., 2016Teufel A. Itzel T. Erhart W. Brosch M. Wang X.Y. Kim Y.O. von Schönfels W. Herrmann A. Brückner S. Stickel F. et al.Gastroenterology. 2016; 151: 513-525.e0Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). Nonetheless, silencing of Taz in hepatocytes by adeno-associated virus-8 (AAV8)-H1-shTaz led to marked diminution in key histologic and serologic features of experimental NASH associated with reduced expression of inflammatory and fibrogenic genes, but had no impact on fasting blood glucose, plasma insulin, or cholesterol. Conversely, overexpression of Taz using AAV8-albumin-Taz led to enhanced histologic features of NASH. Interestingly, Taz was not induced, and Taz silencing had no effect in CCl4 fibrosis, suggesting that its induction may not be a universal feature of liver injury but is instead restricted to models associated with steatosis, inflammation, and fibrosis. To explore the potential link between Taz and fibrosis, Wang et al., 2016Wang Z. Zheng Z. Caviglia J.M. Corey K.E. Herfel T.M. Masia R. Chung R. Lefkowitch J.H. Schwabe R.F. Tabas I. Cell Metab. 2016; 24 (this issue): 848-862Abstract Full Text Full Text PDF Scopus (203) Google Scholar examined whether Indian hedgehog (Ihh), a novel Taz target gene, was induced by Taz in hepatocytes, since another hedgehog ligand, Sonic hedgehog, has been identified as a fibrogenic signal toward hepatic stellate cells, the primary extracellular matrix-producing cell in liver (Michelotti et al., 2013Michelotti G.A. Xie G. Swiderska M. Choi S.S. Karaca G. Krüger L. Premont R. Yang L. Syn W.K. Metzger D. Diehl A.M. J. Clin. Invest. 2013; 123: 2380-2394PubMed Google Scholar). Indeed, ChIP experiments confirmed the interaction of Taz with an enhancer/promoter region in the Ihh gene, and conditioned medium from a rodent hepatocyte line overexpressing Taz drove expression of an artificial reporter containing a responsive element from the Ihh promoter, although no Ihh protein was assessed. This finding was consistent with detection of increased Ihh in human NASH; enhanced expression of Ihh and the Ihh target gene osteopontin in a mouse model of NASH, which was abrogated by Taz silencing in vivo; and, most importantly, prevention of the beneficial effects of Taz silencing on NASH by genetically restoring hepatocyte Ihh in the mouse model. Collectively, the findings convincingly highlight a novel role for Taz in the pathogenesis of experimental NASH (Figure 1) and underscore the need to further clarify its contribution to human disease, including whether Taz in human NASH is de-phosphorylated and nuclear (i.e., transcriptionally active), as it is in the mouse model of NASH. Other questions merit further exploration. The contribution of Taz to NASH may not be restricted to hepatocytes, since hippo signaling has been linked to stellate cell fibrogenesis (Martin et al., 2016Martin K. Pritchett J. Llewellyn J. Mullan A.F. Athwal V.S. Dobie R. Harvey E. Zeef L. Farrow S. Streuli C. et al.Nat. Commun. 2016; 7: 12502Crossref Scopus (125) Google Scholar), and its behavior in other resident and infiltrating cells, especially macrophages, is unknown. Further, the effects of Taz were restricted to inflammation and fibrosis in mice and had no impact on glucose or cholesterol homeostasis or on steatosis, arguing against Taz being an upstream driver of NASH, but rather a downstream mediator. On the other hand, activation of stellate cells initiates its own cascade of inflammatory and metabolic effects, which could include Taz-dependent regulation of the secretion and activity of hedgehog ligands. Upstream signals that lead to Taz activation in NASH need to be defined. Finally, in NASH, hepatocytes are a nexus of metabolic derangements linked to the disease, including fat accumulation, reduced innate immune signaling, antioxidant capacity, and autophagy, and increased endoplasmic reticulum stress leading to the unfolded protein response. How or whether Taz integrates some or all of these inputs merits further evaluation. Because the risk of NASH is in part heritable (Loomba et al., 2015Loomba R. Schork N. Chen C.H. Bettencourt R. Bhatt A. Ang B. Nguyen P. Hernandez C. Richards L. Salotti J. et al.Genetics of NAFLD in Twins ConsortiumGastroenterology. 2015; 149: 1784-1793Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar), it is worth exploring whether genetic variants of Taz might contribute to the variable expression of this disease among patients who are obese. While no polymorphisms of Taz have been linked to NASH thus far, many new gene variants continue to emerge (Dongiovanni et al., 2015Dongiovanni P. Romeo S. Valenti L. BioMed Res. Int. 2015; 2015: 460190Crossref PubMed Scopus (96) Google Scholar). In summary, the findings of Wang et al., 2016Wang Z. Zheng Z. Caviglia J.M. Corey K.E. Herfel T.M. Masia R. Chung R. Lefkowitch J.H. Schwabe R.F. Tabas I. Cell Metab. 2016; 24 (this issue): 848-862Abstract Full Text Full Text PDF Scopus (203) Google Scholar have injected a new player into the complex milieu of NASH pathogenesis. Much like the Looney Toons cartoon character Taz, which depicts an agitated Tasmanian devil, hepatic Taz in NASH is a disruptive force that stirs mayhem. Unlike the fictional cartoon character, however, hepatic Taz is not calmed by music, so the search for therapeutic antagonists of this molecule will need to look elsewhere for more conventional strategies once its contribution to NASH is firmly established. Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic SteatohepatitisWang et al.Cell MetabolismOctober 27, 2016In BriefHepatic fibrosis is a key feature of nonalcoholic steatohepatitis (NASH) affecting morbidity. Wang et al. investigate the underlying mechanisms for progression from benign steatosis to NASH and show that the transcription factor TAZ/WWTR1 is increased in mouse and human NASH. Silencing TAZ can prevent or reverse NASH features, notably fibrosis. Full-Text PDF Open Archive" @default.
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• W2545089922 date "2016-12-01" @default.
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• W2545089922 title "Devilish Effects of Taz in Nonalcoholic Steatohepatitis" @default.
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