P2X7 receptor‐targeted regulation by tetrahydroxystilbene glucoside in alcoholic hepatosteatosis: A new strategy towards macrophage–hepatocyte crosstalk

• Published in: British journal of pharmacology Vol. 177; no. 12; pp. 2793 - 2811
• Main Authors: Zhang, Yu, Jiang, Min, Cui, Ben‐Wen, Jin, Cheng Hua, Wu, Yan‐Ling, Shang, Yue, Yang, Hong‐Xu, Wu, Mei, Liu, Jian, Qiao, Chun‐Ying, Zhan, Zi‐Ying, Ye, Huan, Zheng, Guang‐Hao, Jin, Quan, Lian, Li‐Hua, Nan, Ji‐Xing
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-06-2020; John Wiley and Sons Inc
• Subjects: Calcium influx; Caspase; Ethanol; Hepatocytes; Lipid metabolism; Lipids; Lipopolysaccharides; LKB1 protein; Macrophages; Peritoneum; Receptor mechanisms; Research Paper; Research Papers; SIRT1 protein; Western blotting
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.15007

Background and Purpose
Regulating macrophage–hepatocyte crosstalk through P2X7 receptors has led to new pharmacological strategies to reverse alcoholic hepatosteatosis. We investigated how tetrahydroxystilbene glucoside (2354glu), isolated from Polygonum multiflorum, modulates macrophage–hepatocyte crosstalk during alcoholic hepatosteatosis.
Experimental Approach
A model of alcoholic hepatosteatosis was established by giving ethanol intragastrically to C57BL/6 mice. HepG2 cells were incubated in conditioned medium from LPS+ATP‐activated THP‐1 human macrophages with silenced or overexpressed P2X7 receptors. THP‐1 macrophages or mouse peritoneal macrophages were pretreated with 2354glu for 1 hr prior to LPS+ATP stimulation. Western blots, RT‐PCR and immunohistochemical analysis were used, along with over‐expression and silencing of P2X7 receptors.
Key Results
Knockdown or overexpression of P2X7 receptors in THP‐1 macrophages affected release of mature IL‐1β and, subsequently, modulated lipid metabolism in HepG2 cells via the LKB–AMPK pathway. 2354glu ameliorated alcoholic hepatosteatosis in mice by regulating LKB1–AMPK–SREBP1 pathway and its target genes. Suppression of P2X7 receptor activation by 2354glu inhibited IL‐1β release and reduced macrophage and neutrophil infiltration. In macrophages stimulated with LPS+ATP, expression of P2X7 receptors, caspase‐1 and NF‐κB, release of IL‐1β, calcium influx and PI uptake were reduced by 2354glu. SIRT1–LKB1–AMPK–SREBP1 axis‐mediated lipid accumulation in HepG2 cells was reduced when they were cultured with conditioned media from LPS+ATP‐activated THP‐1 macrophages pretreated with 2354glu.
Conclusion and Implications
Modulation of P2X7 receptors in macrophages regulated lipid accumulation in hepatocytes during alcoholic hepatosteatosis. 2354glu might be a promising candidate that targets P2X7 receptors in macrophages interacting with hepatocytes during alcoholic hepatosteatosis.