Tien Shiuan, Zhou Haoxiong, Zhou Qi, Liu Huiling, Wu Bin, Guo Yunwei
Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China.
Liver Int. 2023 Apr;43(4):840-854. doi: 10.1111/liv.15535. Epub 2023 Feb 28.
BACKGROUND & AIMS: 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.
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）的发生和发展，HCC是一种众所周知的与炎症相关的癌症，有多种病因，包括饮酒。然而，PTTG1在酒精性肝损伤和炎症中的作用尚不清楚。
采集急性酒精中毒患者（n = 20）和健康对照者（n = 20）的血样。对PTTG1基因敲除（KO）小鼠和PTTG1转基因（TG）小鼠单次灌胃酒精（5 g/kg，50%）以构建酒精性肝损伤模型。
我们发现急性ALI患者血清PTTG1水平下调。此外，急性给予酒精显著降低了小鼠血清和肝脏中的PTTG1水平。与野生型小鼠相比，PTTG1 KO小鼠肝损伤更严重，伴有酒精诱导的肝内质网（ER）应激和肝细胞焦亡加重。同样，PTTG1缺乏通过增加肝ER应激和焦亡加剧了原代小鼠肝细胞和LO2细胞中酒精诱导的细胞死亡。重要的是，ER应激抑制剂牛磺熊去氧胆酸（TUDCA）可阻断PTTG1敲低的LO2细胞中酒精诱导的肝焦亡。最后，PTTG1的过表达通过减轻小鼠的ER应激和肝焦亡，显著减轻了酒精诱导的肝损伤。
我们证明PTTG1参与ALI，并对酒精诱导的肝ER应激和焦亡具有保护作用。
