Sirt6 ablation in the liver causes fatty liver that increases cancer risk by upregulating Serpina12

• Published in: EMBO reports 2024-03, Vol.25 (3), p.1361-1386
• Main Authors: Li, Licen, Zeng, Jianming, Zhang, Xin, Feng, Yangyang, Lei, Josh Haipeng, Xu, Xiaoling, Chen, Qiang, Deng, Chu-Xia
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; EMBO21; Life Sciences
• ISSN: 1469-3178; 1469-3178
• DOI: 10.1038/s44319-024-00071-3

Non-alcoholic fatty liver disease is a chronic liver abnormality that exhibits high variability and can lead to liver cancer in advanced stages. 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 Serpina12 as a key gene regulated by Sirt6 that plays a crucial function in energy homeostasis. Specifically, Sirt6 suppresses Serpina12 expression through histone deacetylation at its promoter region, after which the transcription factor, Cebpα, 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 Serpina12 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. Synopsis Sirt6 suppresses Serpina12 in the liver and its deficiency contributes to the onset of liver steatosis and spontaneous tumor development. Sirt6 ablation in the liver causes a lipid-rich environment through upregulation of Serpina12. Cebpα binds to Serpina12 promoter and promotes its expression upon Sirt6 depletion. Deletion of Sirt6 in the liver leads to spontaneous development of tumors and enhanced tumorigenesis in response to DEN treatment or under conditions of obesity. Sirt6 suppresses Serpina12 in the liver and its deficiency contributes to the onset of liver steatosis and spontaneous tumor development.