Deacetylation of BAP31 by sirtuin 2 attenuates apoptosis of hepatocytes induced by endoplasmic reticulum stress, in chronic alcoholic liver injury

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BACKGROUND AND PURPOSE: Endoplasmic reticulum (ER) stress is a crucial pathogenic mechanism in alcoholic liver disease (ALD). B-cell receptor-associated protein 31 (BAP31) can regulate ER homeostasis and anti-apoptosis, but the function and regulation of BAP31 in ALD are unclear. The purpose of this study is to investigate whether BAP31 deacetylation by sirtuin 2 could attenuate ER stress and apoptosis during ALD and to explore whether carnosol could alleviate ALD through the sirtuin 2/BAP31 pathway. EXPERIMENTAL APPROACH: A mouse model of ALD was established by feeding mice with alcoholic liquid chow. In vitro, AML-12 cells were stimulated with alcohol. The therapeutic efficacy of carnosol in protecting mice from ALD pathogenesis was evaluated. KEY RESULTS: Treatment with carnosol protected mice against ALD and attenuated hepatocyte ER stress and apoptosis. Carnosol up-regulated sirtuin 2 expression, and sirtuin 2knockdown abolished the protective effect of carnosol during ALD. Moreover, sirtuin 2 knockdown reduced BAP31 expression. Carnosol-mediated BAP31 up-regulation was abolished upon knockdown of sirtuin 2. Mechanistically, sirtuin 2 selectively regulates the deacetylation of BAP31 at K158. CONCLUSION AND IMPLICATIONS: Taken together, the present study shows for the first time that carnosol exerts its protective efficacy through facilitating sirtuin 2-mediated deacetylation of BAP31 at K158 to attenuate hepatocyte ER stress and apoptosis during ALD. These results provide new therapeutic targets and approaches for combating chronic ALD. LINKED ARTICLES: This article is part of a themed issue Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.20/issuetoc.

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