Blocking ATP-P1Rs axis attenuate alcohol-related liver fibrosis

Aims: The aim of this study was to explore the fibrogenic effects of ATP-P1Rs axis and ATP-P2Rs axis on alcohol-related liver fibrosis (ALF).

Materials and methods: C57BL/6J CD73 knock out (KO) mice were used in our study. 8-12 weeks male mice were used as an ALF model in vivo. In conclusion, after one week of adaptive feeding, 5 % alcohol liquid diet was given for 8 weeks. High-concentration alcohol (31.5 %, 5 g/kg) was administered by gavage twice weekly, and 10 % CCl₄ intraperitoneal injections (1 ml/kg) were administered twice weekly for the last two weeks. The mice in the control group were injected intraperitoneally with an equivalent volume of normal saline. Fasting for 9 h after the last injection, blood samples were collected, and related indicators were tested. In vitro, rat hepatic stellate cells (HSCs) were treated with 200 μM acetaldehyde to establish an alcoholic liver fibrosis for 48 h, then tested related indicators.

Key findings: We found that both adenosine receptors including adenosine A₁, A_2A, A_2B, A₃ receptors (A₁R, A_2AR, A_2BR, A₃R) and ATP receptors including P2X7, P2Y2 receptors (P2X7R, P2Y2R) were expressed increased in ALF. After CD73 was knocked out, we found that adenosine receptors expression decreased, ATP expression increased, and fibrosis degree decreased.

Significance: Based on the research, we discovered that adenosine plays a more important role in ALF. Therefore, blocking the ATP-P1Rs axis represented a potential treatment for ALF, and CD73 will become a potential therapeutic target.

ALF; ATP; Adenosine; P1Rs; P2Rs.