Lee Jaeeun, Woo Hayoung, Kang Hyunju, Park Young-Ki, Lee Ji-Young
Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA.
Department of Food and Nutrition, Keimyung University, Daegu, South Korea.
J Pathol. 2025 Jan;265(1):110-122. doi: 10.1002/path.6372. Epub 2024 Dec 3.
The pathogenesis of alcohol-related liver disease (ALD) is closely linked to mitochondrial dysfunction and impaired cellular energy metabolism. In this study, we explored how ethanol triggers inflammation, oxidative stress, and mitochondrial dysfunction in Kupffer cells, i.e.hepatic resident macrophages, primarily focusing on the mitochondrial unfolded protein response (UPR) using immortalized mouse Kupffer cells (ImKCs) and mouse primary KCs. The UPR is a cellular defense mechanism activated in response to the perturbation of mitochondrial proteostasis to maintain mitochondrial integrity and function by upregulating the expression of mitochondrial chaperones and proteases. We also determined whether nicotinamide riboside (NR), a NAD precursor, could mitigate ethanol-triggered cellular damage. When ImKCs were exposed to 80 mm ethanol for 72 h, they displayed inflammation, oxidative stress, and impaired mitochondrial function with decreased mitochondrial content and deformed mitochondrial crista structure. NR, however, counteracted the effects of ethanol. Furthermore, ethanol increased mRNA and protein levels of UPR genes, such as mitochondrial chaperones and proteases, which were attenuated by NR. Notably, the ethanol-induced shift in the entry of activating transcription factor 5 (ATF5), a putative transcriptional regulator of UPR, to the nucleus from the mitochondria was abolished by NR. The induction of UPR genes by ethanol was significantly repressed when Atf5 was knocked down, indicating the role of ATF5 in the induction of UPR genes in ImKCs exposed to ethanol. We also confirmed the induction of UPR gene expression in mouse and human livers exposed to alcohol. Our findings demonstrate the ability of NR to alleviate ethanol-induced oxidative stress, inflammation, and mitochondrial dysfunction, partly by modulating the ATF5-dependent UPR pathway in ImKCs, suggesting its potential for ALD therapy. © 2024 The Pathological Society of Great Britain and Ireland.
酒精性肝病（ALD）的发病机制与线粒体功能障碍和细胞能量代谢受损密切相关。在本研究中，我们探讨了乙醇如何在库普弗细胞（即肝脏驻留巨噬细胞）中引发炎症、氧化应激和线粒体功能障碍，主要利用永生化小鼠库普弗细胞（ImKCs）和小鼠原代库普弗细胞聚焦于线粒体未折叠蛋白反应（UPR）。UPR是一种细胞防御机制，在响应线粒体蛋白质稳态受到干扰时被激活，通过上调线粒体伴侣蛋白和蛋白酶的表达来维持线粒体的完整性和功能。我们还确定了烟酰胺核糖（NR），一种NAD前体，是否可以减轻乙醇引发的细胞损伤。当ImKCs暴露于80 mM乙醇72小时时，它们表现出炎症、氧化应激和线粒体功能受损，线粒体含量减少且线粒体嵴结构变形。然而，NR抵消了乙醇的影响。此外，乙醇增加了UPR基因（如线粒体伴侣蛋白和蛋白酶）的mRNA和蛋白质水平，而NR减弱了这种增加。值得注意的是，NR消除了乙醇诱导的激活转录因子5（ATF5）（一种假定的UPR转录调节因子）从线粒体进入细胞核的转移。当Atf5被敲低时，乙醇对UPR基因的诱导被显著抑制，表明ATF5在暴露于乙醇的ImKCs中诱导UPR基因的作用。我们还证实了在暴露于酒精的小鼠和人类肝脏中UPR基因表达的诱导。我们的研究结果表明，NR能够减轻乙醇诱导的氧化应激、炎症和线粒体功能障碍，部分是通过调节ImKCs中ATF5依赖的UPR途径，提示其在ALD治疗中的潜力。© 2024英国和爱尔兰病理学会。
