1. P2X7 receptor-targeted regulation by tetrahydroxystilbene glucoside in alcoholic hepatosteatosis: A new strategy towards macrophage-hepatocyte crosstalk.
- Author
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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, Cui, Ben-Wen, Wu, Yan-Ling, Yang, Hong-Xu, and Qiao, Chun-Ying
- Subjects
CROSSTALK ,LIPID metabolism ,GLYCOSIDES ,MACROPHAGES ,CELL metabolism ,WESTERN immunoblotting ,ADENOSINE triphosphate ,RESEARCH ,ANIMAL experimentation ,RESEARCH methodology ,CELL receptors ,INTERLEUKIN-1 ,MEDICAL cooperation ,EVALUATION research ,STILBENE ,COMPARATIVE studies ,EPITHELIAL cells ,MICE - Abstract
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. [ABSTRACT FROM AUTHOR]- Published
- 2020
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