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

IF 7.7 2区医学 Q1 PHARMACOLOGY & PHARMACY British Journal of Pharmacology Pub Date : 2025-01-30 DOI:10.1111/bph.17432

Sai Wang, Yufeng Wang, Wen Shan, Guoyang Li, Ran Yan, Zhecheng Wang, Yan Zhao, Jihong Yao, Ning Zhang

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Abstract

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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在慢性酒精性肝损伤中，sirtuin 2介导BAP31去乙酰化可减轻内质网应激诱导的肝细胞凋亡。

背景与目的：内质网应激是酒精性肝病（ALD）的重要致病机制。b细胞受体相关蛋白31 （BAP31）可调节内质网稳态和抗凋亡，但BAP31在ALD中的功能和调控尚不清楚。本研究旨在探讨sirtuin 2对BAP31去乙酰化是否能减轻ALD时内质膜应激和细胞凋亡，并探讨鼠油醇是否能通过sirtuin 2/BAP31通路缓解ALD。实验方法：用含酒精的液体食物喂养小鼠，建立小鼠ALD模型。体外用酒精刺激AML-12细胞。评价了鼠油醇对小鼠ALD发病机制的保护作用。主要结果：鼠油醇能保护小鼠抗ALD，减轻肝细胞内质网应激和凋亡。鼠油醇上调sirtuin 2的表达，而sirtuin 2的下调则消除了鼠油醇对ALD的保护作用。此外，sirtuin 2敲低可降低BAP31的表达。当sirtuin 2被敲低时，carnosol介导的BAP31上调被取消。在机制上，sirtuin 2选择性地调控K158位点BAP31的去乙酰化。结论和意义：本研究首次表明，鼠油醇通过促进sirtuin 2介导的K158位点BAP31的去乙酰化来发挥其保护作用，以减轻ALD期间肝细胞ER应激和凋亡。这些结果为治疗慢性ALD提供了新的治疗靶点和途径。

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来源期刊

British Journal of Pharmacology 医学-药学

CiteScore

15.40

自引率

12.30%

发文量

270

审稿时长

2.0 months

期刊介绍： The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.