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Hepatic ablation of SIRT6 results in fatty liver disease, yet the potential mechanism of SIRT6 deficiency, particularly in relation to downstream mediators for NAFLD, remains elusive. Here we identify\n                    <jats:italic>Serpina12<\/jats:italic>\n                    as a key gene regulated by\n                    <jats:italic>Sirt6<\/jats:italic>\n                    that plays a crucial function in energy homeostasis. Specifically,\n                    <jats:italic>Sirt6<\/jats:italic>\n                    suppresses\n                    <jats:italic>Serpina12<\/jats:italic>\n                    expression through histone deacetylation at its promoter region, after which the transcription factor, Cebp\u03b1, binds to and regulates its expression. Sirt6 deficiency results in an increased expression of Serpina12 in hepatocytes, which enhances insulin signaling and promotes lipid accumulation. Importantly, CRISPR-Cas9 mediated\n                    <jats:italic>Serpina12<\/jats:italic>\n                    knockout in the liver ameliorated fatty liver disease caused by Sirt6 ablation. Finally, we demonstrate that Sirt6 functions as a tumor suppressor in the liver, and consequently, deletion of Sirt6 in the liver leads to not only the spontaneous development of tumors but also enhanced tumorigenesis in response to DEN treatment or under conditions of obesity.\n                  <\/jats:p>","DOI":"10.1038\/s44319-024-00071-3","type":"journal-article","created":{"date-parts":[[2024,2,8]],"date-time":"2024-02-08T08:03:00Z","timestamp":1707379380000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Sirt6 ablation in the liver causes fatty liver that increases cancer risk by upregulating Serpina12"],"prefix":"10.1038","volume":"25","author":[{"given":"Licen","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9915-8411","authenticated-orcid":false,"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2058-8054","authenticated-orcid":false,"given":"Josh Haipeng","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4213-7956","authenticated-orcid":false,"given":"Qiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8033-3902","authenticated-orcid":false,"given":"Chu-Xia","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,8]]},"reference":[{"key":"71_CR1","doi-asserted-by":"publisher","first-page":"144113","DOI":"10.1016\/j.gene.2019.144113","volume":"721","author":"D Aibara","year":"2019","unstructured":"Aibara D, Matsuo K, Yamano S, Matsusue K (2019) Vaspin is a novel target gene of hepatic CCAAT-enhancer-binding protein. 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