Aldehyde Dehydrogenase 2 Deficiency Impairs Liver Progenitor Cell Proliferation in Alcohol-Fed Mice.

IF 3.6 2区 医学 Q1 PATHOLOGY
Peng Xiao, Siting Yang, Shenghua Bi, Yawen Hao, Feiyu Zhang, Lin Ru, Tao Liu, Shengying Qian, Qiuhong Zai, Ningning Ma, Junqi Niu, Yong He, Yanhang Gao
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Abstract

Aldehyde dehydrogenase 2 (ALDH2) is a critical enzyme involved in the detoxification of acetaldehyde. Although numerous studies have demonstrated the significance of ALDH2 in alcohol-associated liver disease, its role in alcohol-induced activation of liver progenitor cells (LPCs) has not been thoroughly investigated. Proteomic analysis of serum samples from patients with either normal ALDH2 genotype or ALDH2 mutation following alcohol consumption revealed that ALDH2 deficiency may suppress LPC proliferation. To test this hypothesis, Aldh2 knockout (Aldh2KO) mice were generated and fed a 3,5-diethoxycarbonyl1,4-dihydrocollidine-supplemented diet along with 10% ethanol in drinking water. A significant inhibition of LPC proliferation was observed in Aldh2KO mice after alcohol exposure, as indicated by reduced numbers of PanCK- and Ki-67-positive cells in the liver. Bulk RNA sequencing revealed that differentially expressed genes (DEGs) in 3,5-diethoxycarbonyl1,4-dihydrocollidine plus ethanol-fed Aldh2KO mice were enriched in pathways related to inflammation (up-regulated DEGs) and cell cycle suppression (down-regulated DEGs) based on Reactome pathway analysis compared with wild-type mice. Mechanistically, alcohol exposure in Aldh2KO mice led to reduced LPC proliferation, likely mediated by enhanced hepatic pyroptosis and inflammatory responses. In conclusion, these findings suggest that ALDH2 deficiency appears to impair LPC proliferation in alcohol-associated liver disease, highlighting the critical role of ALDH2 in liver regeneration following alcohol-induced injury.

醛脱氢酶2缺乏损害酒精喂养小鼠肝祖细胞增殖。
醛脱氢酶2 (ALDH2)是参与乙醛解毒的关键酶。尽管大量研究已经证明ALDH2在酒精相关性肝病(ALD)中的重要意义,但其在酒精诱导的肝祖细胞(LPCs)活化中的作用尚未得到充分研究。对ALDH2基因型正常或ALDH2基因型突变患者的血清样本进行蛋白质组学分析显示,ALDH2缺乏可能抑制LPC增殖。为了验证这一假设,我们培育了Aldh2敲除(Aldh2KO)小鼠,并给它们喂食添加了3,5-二氧羰基1,4-二氢碰撞碱(DDC)的饮食,同时在饮用水中添加10%的乙醇。酒精暴露后,Aldh2KO小鼠的LPC增殖明显受到抑制,肝脏中panck和ki67阳性细胞数量减少。大量RNA测序(RNA-seq)显示,与野生型(WT)小鼠相比,基于Reactome通路分析,DDC加乙醇喂养的Aldh2KO小鼠中差异表达基因(DEGs)在炎症(DEGs上调)和细胞周期抑制(DEGs下调)相关通路中富集。在机制上,酒精暴露在Aldh2KO小鼠中导致LPC增殖减少,可能是由肝焦亡和炎症反应增强介导的。总之,这些发现表明,ALDH2缺乏似乎会损害ALD中LPC的增殖,突出了ALDH2在酒精诱导损伤后肝脏再生中的关键作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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