DNA损伤调节自噬调节因子1(DRAM1)在炎症和肝细胞凋亡中发挥重要作用,虽然它在酒精相关性肝病(ALD)中的作用,其特征是肝脏炎症和细胞凋亡,还不清楚。在这项研究中,我们探索了表达,角色,和ALD中DRAM1的机制。首先,我们的结果表明,在酒精治疗的早期,小鼠肝脏组织中的DRAM1显着增加。此外,DRAM1敲除减少,肝脏特异性过度表达DRAM1加重,酒精诱导的肝脂肪变性,损伤,小鼠M1巨噬细胞标记物的表达。此外,乙醇诱导的肝细胞DRAM1增加丙酮酸激酶M2(PKM2)富集的细胞外囊泡(EV),来自DRAM1过表达的肝细胞的外体促进巨噬细胞活化。机制研究表明,DRAM1与PKM2相互作用并增加质膜中的PKM2水平。最后,ALD患者肝组织中DRAM1显著升高,与M1巨噬细胞标志物呈正相关。一起来看,这项研究表明,乙醇诱导的肝细胞DRAM1可以增加富含PKM2的EV,促进巨噬细胞活化,并加重ALD的疾病进展。这些结果表明,DRAM1可能是ALD治疗的潜在有希望的靶标。
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.