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Hepatic stellate cells (HSCs) have been suggested to play a major role in liver fibrosis. However, the molecular mechanisms remain incompletely understood. Sirtuin 6 (SIRT6), an NAD\n                    <jats:sup>+<\/jats:sup>\n                    \u2010dependent deacetylase, has been previously implicated in the regulation of the transforming growth factor \u03b2 (TGF\u03b2)\u2010SMAD3 pathway that plays a significant role in liver fibrosis. In this work, we aimed to identify other important players during hepatic fibrogenesis, which are modulated by SIRT6. Yes\u2010associated protein (YAP) and transcriptional coactivator with PDZ\u2010binding motif (TAZ or WWTR1), key players in the Hippo pathway, have been implicated in the promotion of hepatic fibrosis. Our data show that HSC\u2010specific Sirt6 knockout mice are more susceptible to high\u2010fat\u2010cholesterol\u2010cholate diet\u2010induced hepatic fibrosis than their wildtype counterparts. Our signaling analyses suggest that in addition to the TGF\u03b2\u2010SMAD3 pathway, YAP and TAZ are also highly activated in the SIRT6\u2010deficient HSCs. As it is not clear how SIRT6 might regulate YAP and TAZ, we have decided to elucidate the mechanism underlying the regulation of YAP and TAZ by SIRT6 in HSCs. Overexpression or knockdown of SIRT6 corroborates the role of SIRT6 in the negative regulation of YAP and TAZ. Further biochemical analyses reveal that SIRT6 deacetylates YAP and TAZ and reprograms the composition of the TEA domain transcription factor complex to suppress their downstream target genes, particularly those involved in hepatic fibrosis. In conclusion, our data suggest that SIRT6 plays a critical role in the regulation of the Hippo pathway to protect against hepatic fibrosis.\n                  <\/jats:p>","DOI":"10.1096\/fj.202200522r","type":"journal-article","created":{"date-parts":[[2022,8,29]],"date-time":"2022-08-29T08:36:50Z","timestamp":1661762210000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Sirtuin 6 protects against hepatic fibrogenesis by suppressing the\n                    <scp>YAP<\/scp>\n                    and\n                    <scp>TAZ<\/scp>\n                    function"],"prefix":"10.1096","volume":"36","author":[{"given":"Kushan","family":"Chowdhury","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menghao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeong\u2010Geug","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Indiana University School of Medicine  Indianapolis Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5452-6882","authenticated-orcid":false,"given":"X. Charlie","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Center for Computational Biology and Bioinformatics Indiana University School of Medicine  Indianapolis Indiana USA"},{"name":"Center for Diabetes and Metabolic Diseases Indiana University School of Medicine  Indianapolis Indiana 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