Unknown

Dataset Information

0

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.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC8511299 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC10443796 | biostudies-literature
| S-EPMC10520483 | biostudies-literature
| S-EPMC3628968 | biostudies-literature
| S-EPMC7132198 | biostudies-literature
| S-EPMC8461381 | biostudies-literature
| S-EPMC9875677 | biostudies-literature
| S-EPMC6759817 | biostudies-literature
| S-EPMC6786423 | biostudies-literature
| S-EPMC5758662 | biostudies-literature
| S-EPMC4930699 | biostudies-literature