AUTHOR=Liu Zhenni , Wu Xue , Wang Qi , Li Zixuan , Liu Xueqi , Sheng Xiaodong , Zhu Hong , Zhang Mengda , Xu Junrui , Feng Xiaowen , Wu Baoming , Lv Xiongwen 

TITLE=CD73-Adenosine A1R Axis Regulates the Activation and Apoptosis of Hepatic Stellate Cells Through the PLC-IP3-Ca2+/DAG-PKC Signaling Pathway

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.922885

DOI=10.3389/fphar.2022.922885

ISSN=1663-9812

ABSTRACT=Alcohol-related liver fibrosis (ALF) is a kind of alcohol- related liver disease and responds to long-term heavy drinking. CD73, also called ecto-5’-nucleotidase (NT5E), is an ectomembrane protein linked to a cell membrane via the GPI anchor that regulates the conversion of extracellular ATP to adenosine. Adenosine and its receptors are also known as key regulators in cellular responses. Our previous studies have shown that CD73 and adenosine A1 receptor (A1R) have an important role in alcohol-related liver disease, but its specific mechanism is still unclear. This study sought to explore the role and mechanism of CD73-A1R axis in a murine model of alcohol and CCl4 induced ALF and in an in vitro model of fibrosis induced by acetaldehyde. The degree of liver injury was measured by detecting serum AST and ALT contents and H&E staining and Masson staining. The expression levels of fibrosis indicators and the PLC-IP3-Ca2+/DAG-PKC signaling pathway were detected by quantitative real-time PCR, Western blot, ELISA and calcium assay. Hepatic stellate cell (HSC) apoptosis was detected by an Annexin V-FITC/PI cell apoptosis detection kit. Knockdown of CD73 significantly attenuates the accumulation of α-SMA and collagen I and damaged histological architecture in mice liver induced by alcohol and CCl4. In vitro, inhibition of CD73 attenuated acetaldehyde-induced fibrosis and downregulated A1R expression in HSC-T6 cell. Meanwhile, the inhibition of CD73/A1R can downregulate the expression of PLC-IP3-Ca2+/DAG-PKC signaling pathway. In addition, silencing of CD73/A1R can promote the apoptosis of HSC-T6 cell. In conclusion, CD73-A1R axis can regulate the activation and apoptosis of hepatic stellate cells through the PLC-IP3-Ca2+/DAG-PKC signaling pathway.