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Abstract
Protein acetylation has emerged to play pivotal roles in alcoholic liver disease (ALD). Sirutin 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase involved in the regulation of aging, metabolism, and stress. However, the role of SIRT2 in ALD remains unclear. Here, we report that the SIRT2-mediated deacetylation–deubiquitination switch of CCAAT/enhancer-binding protein beta (C/EBPβ) prevents ALD. Our results showed that hepatic SIRT2 protein expression was negatively correlated with the severity of alcoholic liver injury in ALD patients. Liver-specific SIRT2 deficiency sensitized mice to ALD, whereas transgenic SIRT2 overexpression in hepatocytes significantly prevented ethanol-induced liver injury via normalization of hepatic steatosis, lipid peroxidation, and hepatocyte apoptosis. Mechanistically, we identified C/EBPβ as a critical substrate of SIRT2 implicated in ALD. SIRT2-mediated deacetylation at lysines 102 and 211 decreased C/EBPβ ubiquitination, resulting in enhanced protein stability and subsequently increased transcription of C/EBPβ-target gene LCN2. Importantly, hepatic deacetylated C/EBPβ and LCN2 compensation reversed SIRT2 deletion-induced ALD aggravation in mice. Furthermore, C/EBPβ protein expression was positively correlated with SIRT2 and LCN2 expression in the livers of ALD patients and was inversely correlated with ALD development. Therefore, activating SIRT2-C/EBPβ-LCN2 signaling pathway is a potential therapy for ALD.
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1 Shanghai Jiao Tong University School of Medicine, Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293)
2 The Affiliated Hospital of Youjiang Medical University for Nationalities, Department of Pathology, Baise, Guangxi, China (GRID:grid.460081.b)
3 Shanghai Jiao Tong University School of Medicine, Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293)
4 Shanghai Jiao Tong University, Department of Orthopedics, Shanghai General Hospital, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293)
5 Shanghai Jiao Tong University School of Medicine, Department of Core Facility of Basic Medical Sciences, Shanghai, China (GRID:grid.16821.3c) (ISNI:0000 0004 0368 8293)