DRAM1 increases the secretion of PKM2-enriched EVs from hepatocytes to promote macrophage activation and disease progression in ALD

Molecular Therapy: Nucleic Acids

Likun Zhuang¹  Kai Liu²  Shousheng Liu³  Zhenzhen Zhao³  Jie Zhang⁴  Yifen Wang⁴  Mengzhen Dong⁴  Lizhen Chen⁴  Mengke Wang⁴  Baokai Sun⁴  Yongning Xin⁴  Xuefeng Ma⁴  Wenwen Jin⁴  Jie Tan⁴ 

[1] Corresponding author: Yongning Xin, Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071 China.;Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China;Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao 266071, China;Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao 266011, China;

关键词: Alcohol-related liver disease;    DRAM1;    Extracellular vesicles;    PKM2;    Macrophage activation;   

DOI  :  

来源: DOAJ

【 摘 要 】

DNA damage-regulated autophagy modulator 1 (DRAM1) could play important roles in inflammation and hepatic apoptosis, while its roles in alcohol-related liver disease (ALD), which is characterized by hepatic inflammation and apoptosis, are still unclear. In this study, we explored the expression, role, and mechanism of DRAM1 in ALD. Firstly, our results showed that DRAM1 was significantly increased in liver tissues of mice at the early stage of alcohol treatment. In addition, DRAM1 knockout reduced, and liver-specific overexpression of DRAM1 aggravated, alcohol-induced hepatic steatosis, injury, and expressions of M1 macrophage markers in mice. Furthermore, ethanol-induced DRAM1 of hepatic cells increased pyruvate kinase M2 (PKM2)-enriched extracellular vesicles (EVs), and ectosomes derived from hepatic cells with DRAM1 overexpression promoted macrophage activation. Mechanistic investigations showed that DRAM1 interacted with PKM2 and increased the PKM2 level in plasma membrane. At last, DRAM1 was significantly increased in liver tissues of ALD patients, and it was positively correlated with M1 macrophage markers. Taken together, this study revealed that ethanol-induced DRAM1 of hepatic cells could increase the PKM2-enriched EVs, promote macrophage activation, and aggravate the disease progression of ALD. These findings suggested that DRAM1 might be a potentially promising target for the therapy of ALD.

【 授权许可】

Unknown