Abstract：
Heavy drinking is a primary cause of alcoholic liver injury (ALI). Pituitary tumour transforming gene 1 (PTTG1) is involved in the occurrence and development of hepatocellular carcinoma (HCC), which is a well-known inflammation-related cancer with various aetiologies, including alcohol consumption. However, the role of PTTG1 in alcohol-induced liver injury and inflammation is not clear.
Blood samples were collected from patients with acute alcohol intoxication (n = 20) and healthy controls (n = 20). PTTG1 knockout (KO) mice and PTTG1 transgenic (TG) mice were given a single gavage of alcohol (5 g/kg, 50%) to construct the alcohol-induced liver injury.
We found that serum PTTG1 levels were downregulated in acute ALI patients. In addition, acute alcohol administration significantly reduced PTTG1 levels in the serum and liver of mice. Compared to wild-type mice, PTTG1 KO mice had more serious liver injury, which was accompanied by worsened hepatic endoplasmic reticulum (ER) stress and hepatocyte pyroptosis induced by alcohol. Similarly, PTTG1 deficiency exacerbated alcohol-induced cell death in primary mouse hepatocytes and LO2 cells, by increasing hepatic ER stress and pyroptosis. Importantly, TUDCA, an ER stress inhibitor, could blocked alcohol-induced hepatic pyroptosis in PTTG1 knockdown LO2 cells. Finally, overexpression of PTTG1 substantially attenuated alcohol-induced liver injury by reducing ER stress and hepatic pyroptosis in mice.
We demonstrated that PTTG1 participates in ALI and has a protective effect against alcohol-induced hepatic ER stress and pyroptosis.
Blood samples were collected from patients with acute alcohol intoxication (n = 20) and healthy controls (n = 20). PTTG1 knockout (KO) mice and PTTG1 transgenic (TG) mice were given a single gavage of alcohol (5 g/kg, 50%) to construct the alcohol-induced liver injury.
We found that serum PTTG1 levels were downregulated in acute ALI patients. In addition, acute alcohol administration significantly reduced PTTG1 levels in the serum and liver of mice. Compared to wild-type mice, PTTG1 KO mice had more serious liver injury, which was accompanied by worsened hepatic endoplasmic reticulum (ER) stress and hepatocyte pyroptosis induced by alcohol. Similarly, PTTG1 deficiency exacerbated alcohol-induced cell death in primary mouse hepatocytes and LO2 cells, by increasing hepatic ER stress and pyroptosis. Importantly, TUDCA, an ER stress inhibitor, could blocked alcohol-induced hepatic pyroptosis in PTTG1 knockdown LO2 cells. Finally, overexpression of PTTG1 substantially attenuated alcohol-induced liver injury by reducing ER stress and hepatic pyroptosis in mice.
We demonstrated that PTTG1 participates in ALI and has a protective effect against alcohol-induced hepatic ER stress and pyroptosis.
摘要：
目的：大量饮酒是酒精性肝损伤（ALI）的主要原因。垂体肿瘤转化基因1(PTTG1)参与肝细胞癌(HCC)的发生发展,这是一种众所周知的炎症相关癌症，有各种病因，包括酒精消费。然而,PTTG1在酒精性肝损伤和炎症中的作用尚不清楚。
方法：收集急性酒精中毒患者（n=20）和健康对照（n=20）的血样。PTTG1敲除(KO)小鼠和PTTG1转基因(TG)小鼠给予单次灌胃酒精(5g/kg,50%)构建了酒精性肝损伤。
结果：我们发现急性ALI患者血清PTTG1水平下调。此外,急性酒精显著降低小鼠血清和肝脏中PTTG1的水平。与野生型（WT）小鼠相比，PTTG1基因敲除（KO）小鼠肝损伤较严重，伴随着酒精诱导的肝内质网（ER）应激和肝细胞焦亡的恶化。同样，PTTG1缺乏加剧了酒精诱导的原代小鼠肝细胞和LO2细胞死亡，通过增加肝内质网应激和焦亡。重要的是,TUDCA,ER应激抑制剂，可以阻断乙醇诱导的PTTG1敲低LO2细胞的肝焦凋亡。最后,PTTG1的过表达通过减少小鼠内质网应激和肝脏焦亡而显著减轻酒精诱导的肝损伤。
结论：我们证明PTTG1参与ALI，并对酒精诱导的肝内质网应激和细胞凋亡具有保护作用。
方法：收集急性酒精中毒患者（n=20）和健康对照（n=20）的血样。PTTG1敲除(KO)小鼠和PTTG1转基因(TG)小鼠给予单次灌胃酒精(5g/kg,50%)构建了酒精性肝损伤。
结果：我们发现急性ALI患者血清PTTG1水平下调。此外,急性酒精显著降低小鼠血清和肝脏中PTTG1的水平。与野生型（WT）小鼠相比，PTTG1基因敲除（KO）小鼠肝损伤较严重，伴随着酒精诱导的肝内质网（ER）应激和肝细胞焦亡的恶化。同样，PTTG1缺乏加剧了酒精诱导的原代小鼠肝细胞和LO2细胞死亡，通过增加肝内质网应激和焦亡。重要的是,TUDCA,ER应激抑制剂，可以阻断乙醇诱导的PTTG1敲低LO2细胞的肝焦凋亡。最后,PTTG1的过表达通过减少小鼠内质网应激和肝脏焦亡而显著减轻酒精诱导的肝损伤。
结论：我们证明PTTG1参与ALI，并对酒精诱导的肝内质网应激和细胞凋亡具有保护作用。
