Alcohol Metabolism Potentiates HIV-Induced Hepatotoxicity: Contribution to End-Stage Liver Disease
Alcohol Metabolism Potentiates HIV-Induced Hepatotoxicity: Contribution to End-Stage Liver Disease
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DOI：
10.3390/biom9120851
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发表时间：
2019-12-01
期刊：
影响因子：
5.5
通讯作者：
Osna, Natalia A.
中科院分区：
文献类型：
--
作者：
Ganesan, Murali;New-Aaron, Moses;Osna, Natalia A.
在由于现代抗逆转录病毒治疗而提高存活率的时代，肝病已成为发病率和死亡率的主要原因，导致15-17%的人类免疫缺陷病毒（HIV）感染患者死亡。酒精会增强HIV介导的肝损伤，并促进进展为晚期纤维化和肝硬化。然而，这些事件背后的机制尚不确定。在这里，我们假设乙醇代谢增强了HIV在肝细胞中的积累，导致氧化应激和密集的凋亡细胞死亡。非实质细胞（NPC）吞噬含HIV的凋亡肝细胞触发其激活和肝损伤进展。这项研究是在感染HIV-1ADA的原代人肝细胞和Huh7.5-hepatocellular细胞上进行的，主要发现得到了用乙醇喂养的HIV注射嵌合小鼠人源化肝脏的初步数据的证实。我们证明了乙醇暴露通过抑制溶酶体和蛋白酶体对HIV的降解而增强HIV在肝细胞中的积累。这导致氧化应激和肝细胞凋亡增加。HIV感染的凋亡肝细胞暴露于NPC激活巨噬细胞中的炎性小体和肝星状细胞中的促纤维化基因。我们的结论是，虽然HIV和乙醇代谢触发的细胞凋亡清除HIV感染的肝细胞，HIV表达的凋亡小体的持续产生可能是有害的肝脏炎症和纤维化的进展，由于不断激活的NPC。
In an era of improved survival due to modern antiretroviral therapy, liver disease has become a major cause of morbidity and mortality, resulting in death in 15-17% of human immunodeficiency virus (HIV)-infected patients. Alcohol enhances HIV-mediated liver damage and promotes the progression to advanced fibrosis and cirrhosis. However, the mechanisms behind these events are uncertain. Here, we hypothesize that ethanol metabolism potentiates accumulation of HIV in hepatocytes, causing oxidative stress and intensive apoptotic cell death. Engulfment of HIV-containing apoptotic hepatocytes by non-parenchymal cells (NPCs) triggers their activation and liver injury progression. This study was performed on primary human hepatocytes and Huh7.5-CYP cells infected with HIV-1ADA, and major findings were confirmed by pilot data obtained on ethanol-fed HIV-injected chimeric mice with humanized livers. We demonstrated that ethanol exposure potentiates HIV accumulation in hepatocytes by suppressing HIV degradation by lysosomes and proteasomes. This leads to increased oxidative stress and hepatocyte apoptosis. Exposure of HIV-infected apoptotic hepatocytes to NPCs activates the inflammasome in macrophages and pro-fibrotic genes in hepatic stellate cells. We conclude that while HIV and ethanol metabolism-triggered apoptosis clears up HIV-infected hepatocytes, continued generation of HIV-expressing apoptotic bodies may be detrimental for progression of liver inflammation and fibrosis due to constant activation of NPCs.