PTTG1 alleviates acute alcoholic liver injury by inhibiting endoplasmic reticulum stress-induced hepatocyte pyroptosis.

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 (5g/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.