Astaxanthin Protects against Alcoholic Liver Injury via Regulating Mitochondrial Redox Balance and Calcium Homeostasis
Astaxanthin Protects against Alcoholic Liver Injury via Regulating Mitochondrial Redox Balance and Calcium Homeostasis
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DOI：
10.1021/acs.jafc.3c05529
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发表时间：
2023-12-01
影响因子：
6.1
通讯作者：
Liang，Hui
中科院分区：
文献类型：
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作者：
Wang，Peng;Zheng，Xian;Liang，Hui
越来越多的证据表明，线粒体功能障碍引发的钙超载在酒精性肝病（ALD）的发展中起着关键作用。线粒体作为有氧呼吸的重要细胞器，具有双层膜，是酒精代谢介导的脂质过氧化作用的关键靶点，其中线粒体特异性磷脂心磷脂氧化为4-羟基壬烯醛（4-HNE）最终导致线粒体完整性和功能受损。因此，确定针对线粒体氧化还原功能的有效营养干预对于ALD的替代疗法是绝对必要的，以弥补由于成瘾而难以实现酒精戒断的困难。本研究通过细胞实验证实了虾青素（AX）在各种类胡萝卜素中抗酒精毒性的显著优势，并通过生物信息学分析确定了其在细胞形态建成和钙信号通路中的潜力。建立SD大鼠酒精性肝损伤模型，观察AX对酒精性肝损伤的保护作用，并探讨其作用机制。AX干预减弱了酒精诱导的氧化应激和脂质过氧化以及以退行性形态变化和膜电位塌陷为特征的线粒体功能障碍。此外，AX通过激活与线粒体氧化还原平衡密切相关的Nrf 2-ARE信号通路减少4-HNE的产生。此外，在体内和体外观察到AX引起的线粒体Ca 2+积聚减轻。此外，我们揭示了AX和线粒体膜通道蛋白MCU和VDAC 1的结构-活性关系，暗示潜在的作用靶标。总之，我们的数据表明了AX干预的新机制，通过恢复线粒体中的氧化还原平衡和Ca 2+稳态来保护酒精诱导的肝损伤，并为AX作为ALD管理的治疗选择的发展提供了新的见解。
Increasing evidence points to the critical role of calcium overload triggered by mitochondrial dysfunction in the development of alcoholic liver disease (ALD). As an important organelle for aerobic respiration with a double-layered membrane, mitochondria are pivotal targets of alcohol metabolism-mediated lipid peroxidation, wherein mitochondria-specific phospholipid cardiolipin oxidation to 4-hydroxynonenal (4-HNE) ultimately leads to mitochondrial integrity and function impairment. Therefore, it is absolutely essential to identify effective nutritional intervention targeting mitochondrial redox function for an alternative therapy of ALD, in order to compensate for the difficulty in achieving alcohol withdrawal due to addiction. In this study, we confirmed the significant advantages of astaxanthin (AX) against alcohol toxicity among various carotenoids via cell experiments and identified the potential in mitochondrion morphogenesis and calcium signaling pathway by bioinformatics analysis. The ALD model of Sprague–Dawley (SD) rats was also generated to investigate the effectiveness of AX on alcohol-induced liver injury, and the underlying mechanisms were further explored. AX intervention attenuated alcohol-induced oxidative stress and lipid peroxidation as well as mitochondrial dysfunction characterized by degenerative morphology changes and collapsed membrane potential. Also, AX reduced the production of 4-HNE by activating the Nrf2-ARE signaling pathway, which is closely associated with the redox balance of mitochondria. In addition, relieved mitochondrial Ca2+accumulation caused by AX was observed both in vivo and in vitro. Furthermore, we revealed the structure–activity relationship of AX and mitochondrial membrane channel proteins MCU and VDAC1, implying potential acting targets. Altogether, our data indicated a new mechanism of AX intervention which protects against alcohol-induced liver injury through restoring redox balance and Ca2+homeostasis in mitochondria, as well as provided novel insights into the development of AX as a therapeutic option for the management of ALD.