SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury

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.

Transcriptome-Wide Gene-Gene Interaction Association Study Elucidates Pathways and Functional Enrichment of Complex Traits

“…G-protein mediated event genes were enriched for pAUDIT, which includes signal transduction at the synapse, and is consistent with the WNT6-PRKCG interaction noted above (and possible immune function). Gene interactions within the deubiquitination REACTOME pathway were associated with pAUDIT, suggesting the importance of post-translational modification in alcohol use as has been hypothesized 67 , and highlighting the need for additional 'omics integration into such analyses. Notably, three of the coexpression network modules identified by Gandal et al 30,64 were associated with BMI or pAUDIT.…”

Hepatocyte-specific deletion of cellular repressor of E1A-stimulated genes 1 exacerbates alcohol-induced liver injury by activating stress kinases

“…It is reported that p38MAPK mediates the stress signal to induce senescence 41 . Previous studies have reported that several genes that regulate aging are involved in the development of ALD, such as SIRT1, SIRT2 and SIRT6 42 - 44 . Importantly, CREG1 is also involved in the ageing process 10 , 11 .…”

Tenovin-1 Ameliorates Renal Fibrosis in High-Fat-Diet-Induced Diabetic Nephropathy via Antioxidant and Anti-Inflammatory Pathways

“…The upregulation of SIRT2 was found in HFD-fed rats compared with rats fed a normal diet [ 96 , 97 ]. The present study revealed that SIRT1 and claudin-1 expressions showed opposite trends in the HFD-fed rat kidneys.…”