Ferdouse Afroza, Clugston Robin D
Department of Physiology, University of Alberta, Edmonton, AB, Canada.
Front Physiol. 2022 Jul 5;13:940974. doi: 10.3389/fphys.2022.940974. eCollection 2022.
Alcohol-associated liver disease (ALD) is a major public health issue that significantly contributes to human morbidity and mortality, with no FDA-approved therapeutic intervention available. The health burden of ALD has worsened during the COVID-19 pandemic, which has been associated with a spike in alcohol abuse, and a subsequent increase in hospitalization rates for ALD. A key knowledge gap that underlies the lack of novel therapies for ALD is a need to better understand the pathogenic mechanisms that contribute to ALD initiation, particularly with respect to hepatic lipid accumulation and the development of fatty liver, which is the first step in the ALD spectrum. The goal of this review is to evaluate the existing literature to gain insight into the pathogenesis of alcohol-associated fatty liver, and to synthesize alcohol's known effects on hepatic lipid metabolism. To achieve this goal, we specifically focus on studies from transgenic mouse models of ALD, allowing for a genetic dissection of alcohol's effects, and integrate these findings with our current understanding of ALD pathogenesis. Existing studies using transgenic mouse models of ALD have revealed roles for specific genes involved in hepatic lipid metabolic pathways including fatty acid uptake, mitochondrial β-oxidation, lipogenesis, triglyceride metabolism, and lipid droplet formation. In addition to reviewing this literature, we conclude by identifying current gaps in our understanding of how alcohol abuse impairs hepatic lipid metabolism and identify future directions to address these gaps. In summary, transgenic mice provide a powerful tool to understand alcohol's effect on hepatic lipid metabolism and highlight that alcohol abuse has diverse effects that contribute to the development of alcohol-associated fatty liver disease.
酒精性肝病（ALD）是一个重大的公共卫生问题，对人类的发病率和死亡率有重大影响，目前尚无美国食品药品监督管理局（FDA）批准的治疗干预措施。在新冠疫情期间，ALD的健康负担有所加重，这与酒精滥用的激增以及随后ALD住院率的上升有关。导致ALD缺乏新疗法的一个关键知识空白是，需要更好地了解导致ALD发病的致病机制，特别是关于肝脏脂质积累和脂肪肝的发展，而脂肪肝是ALD病程的第一步。这篇综述的目的是评估现有文献，以深入了解酒精性脂肪肝的发病机制，并综合酒精对肝脏脂质代谢的已知影响。为实现这一目标，我们特别关注来自ALD转基因小鼠模型的研究，以便对酒精的作用进行基因剖析，并将这些发现与我们目前对ALD发病机制的理解相结合。现有的使用ALD转基因小鼠模型的研究揭示了参与肝脏脂质代谢途径的特定基因的作用，包括脂肪酸摄取、线粒体β-氧化、脂肪生成、甘油三酯代谢和脂滴形成。除了综述这些文献外，我们还通过确定目前在理解酒精滥用如何损害肝脏脂质代谢方面的差距来得出结论，并确定解决这些差距的未来方向。总之，转基因小鼠为理解酒精对肝脏脂质代谢的影响提供了一个有力的工具，并突出表明酒精滥用具有多种作用，这些作用促成了酒精性脂肪肝病的发展。
