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

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. 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 for the therapy of ALD.

Automated summary

In this study, the expression, role, and mechanism of DRAM1 in alcohol-related liver disease (ALD) were investigated. The results showed that DRAM1 was significantly increased in the liver tissues of mice at the early stage of alcohol treatment. DRAM1 knockout reduced the symptoms of ALD, while liver-specific overexpression of DRAM1 aggravated them. Furthermore, ethanol-induced DRAM1 of hepatic cells increased extracellular vesicles (EVs) enriched with pyruvate kinase M2 (PKM2) and promoted macrophage activation.