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P2X7 receptor-targeted regulation by tetrahydroxystilbene glucoside in alcoholic hepatosteatosis: A new strategy towards macrophage-hepatocyte crosstalk.
- Source :
-
British Journal of Pharmacology . Jun2020, Vol. 177 Issue 12, p2793-2811. 19p. 1 Diagram, 9 Graphs. - Publication Year :
- 2020
-
Abstract
- <bold>Background and Purpose: </bold>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.<bold>Experimental Approach: </bold>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.<bold>Key Results: </bold>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.<bold>Conclusion and Implications: </bold>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]
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 00071188
- Volume :
- 177
- Issue :
- 12
- Database :
- Academic Search Index
- Journal :
- British Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 143330348
- Full Text :
- https://doi.org/10.1111/bph.15007