Chen Yunling, Zhang Dongyuan, Wu Yunxiao, Jiang Wenshan, Guo Luoting, Pan Di, He Qiao, Yin Zhaoqing, Sun Lichao, Wang Shuanglian
Science and Technology Innovation Center, Shandong First Medical University, Jinan, People's Republic of China.
Medical School, Nankai University, Tianjin, People's Republic of China.
Am J Physiol Gastrointest Liver Physiol. 2025 May 1;328(5):G610-G623. doi: 10.1152/ajpgi.00283.2024. Epub 2025 Apr 17.
Alcohol-related liver disease (ALD) is one of the leading causes of alcohol-related morbidity and mortality worldwide. Unfortunately, limited therapeutic options are currently available, due to the complex risk factors involved as well as the lack of information on the molecular mechanisms driving its progression. Interestingly, chronic, excessive alcohol intake has been reported to exacerbate the severity of obstructive sleep apnea (OSA), a respiratory disorder typically characterized by chronic intermittent hypoxia (CIH). However, this relationship between alcohol-enhanced OSA and ALD development/progression remains to be elucidated. As an approach to investigate this relationship, in vivo Gao-binge ALD and CIH mouse models were established. Alcohol-related liver injury, hepatic steatosis, inflammation, and oxidative stress were then assessed in these models. In addition, lipopolysaccharide (LPS) and ethanol-cotreated mouse normal hepatocyte cell line AML12 served as an in vitro model to investigate the mechanisms through which CIH affects ethanol-induced liver injury. CIH intervention ameliorated alcohol-related liver injury, reduced hepatic lipid accumulation and oxidative stress, and alleviated liver inflammation. Mechanistically, in the liver of these Gao-binge mice, CIH intervention inhibited alcohol-induced upregulation and activation of hypoxia-inducible factor 2α (HIF-2α), a protein which plays a key role in hepatic lipid metabolism and liver injury. Similar to these effects observed in response to CIH intervention, treatment of Gao-binge mice with the selective inhibitor of HIF-2α, PT2385, alleviated alcohol-related liver injury and steatosis while inhibiting oxidative stress and inflammation. Additional findings from our in vitro model revealed that CIH downregulated HIF-2α by promoting calpains protein expression, thereby reducing the accumulation of lipid droplets and decreasing reactiveoxygenspecies (ROS) production in AML12 cells co-challenged with LPS and ethanol. The above results provide important, new evidence that reconceptualizes the role of alcohol-enhanced OSA in ALD progression. Moreover, these findings can serve as the foundation for the development of HIF-2α inhibitors for use in the prevention and treatment of ALD. Chronic intermittent hypoxia (CIH) intervention mitigated hepatic lipid accumulation and reduced hepatic injury, inflammation, and oxidative stress in alcohol-related liver disease (ALD) mice. CIH alleviates ALD and is likely linked to the downregulation of hypoxia-inducible factor 2α (HIF-2α) expression mediated by calpains. This study presents a new possibility for ALD treatment and lays a theoretical foundation for the clinical treatment of ALD.
酒精性肝病（ALD）是全球范围内与酒精相关的发病和死亡的主要原因之一。不幸的是，由于涉及的复杂风险因素以及缺乏关于驱动其进展的分子机制的信息，目前可用的治疗选择有限。有趣的是，据报道，长期过量饮酒会加剧阻塞性睡眠呼吸暂停（OSA）的严重程度，OSA是一种通常以慢性间歇性缺氧（CIH）为特征的呼吸系统疾病。然而，酒精增强的OSA与ALD发展/进展之间的这种关系仍有待阐明。作为研究这种关系的一种方法，建立了体内高剂量暴饮酒精性肝病和CIH小鼠模型。然后在这些模型中评估酒精相关的肝损伤、肝脂肪变性、炎症和氧化应激。此外，脂多糖（LPS）和乙醇共同处理的小鼠正常肝细胞系AML12用作体外模型，以研究CIH影响乙醇诱导的肝损伤的机制。CIH干预改善了酒精相关的肝损伤，减少了肝脏脂质积累和氧化应激，并减轻了肝脏炎症。从机制上讲，在这些高剂量暴饮酒精小鼠的肝脏中，CIH干预抑制了酒精诱导的缺氧诱导因子2α（HIF-2α）的上调和激活，HIF-2α是一种在肝脏脂质代谢和肝损伤中起关键作用的蛋白质。与CIH干预观察到的这些效应相似，用HIF-2α的选择性抑制剂PT2385治疗高剂量暴饮酒精小鼠，减轻了酒精相关的肝损伤和脂肪变性，同时抑制了氧化应激和炎症。我们体外模型的其他发现表明，CIH通过促进钙蛋白酶蛋白表达下调HIF-2α，从而减少与LPS和乙醇共同挑战的AML12细胞中脂滴的积累并降低活性氧（ROS）的产生。上述结果提供了重要的新证据，重新认识了酒精增强的OSA在ALD进展中的作用。此外，这些发现可作为开发用于预防和治疗ALD的HIF-2α抑制剂的基础。慢性间歇性缺氧（CIH）干预减轻了酒精性肝病（ALD）小鼠的肝脏脂质积累，减少了肝损伤、炎症和氧化应激。CIH减轻了ALD，可能与钙蛋白酶介导的缺氧诱导因子2α（HIF-2α）表达下调有关。本研究为ALD治疗提供了新的可能性，为ALD的临床治疗奠定了理论基础。
