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

Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE

Publication: London : Wiley
Original Publication: London, Macmillian Journals Ltd.

Macrophages*/metabolism ; Receptors, Purinergic P2X7*; Adenosine Triphosphate ; Animals ; Glucosides ; Hepatocytes/metabolism ; Interleukin-1beta/metabolism ; Mice ; Mice, Inbred C57BL ; Stilbenes

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.
(© 2020 The British Pharmacological Society.)

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81560597 National Natural Science Foundation of China; 81660689 National Natural Science Foundation of China; 81860751 National Natural Science Foundation of China; 81960677 National Natural Science Foundation of China; JJKH20191155KJ Science and Technology Planning Project of the Jilin Provincial Education Department; 20180201065YY Science and Technology Planning Projects from the Science and Technology Department of Jilin Province; 20180414048GH Science and Technology Planning Projects from the Science and Technology Department of Jilin Province; 20180519010JH Science and Technology Planning Projects from the Science and Technology Department of Jilin Province

0 (2',3',4',5'-tetrahydroxystilbene-2-O-beta-D-glucoside)
0 (Glucosides)
0 (Interleukin-1beta)
0 (Receptors, Purinergic P2X7)
0 (Stilbenes)
8L70Q75FXE (Adenosine Triphosphate)

Date Created: 20200206 Date Completed: 20210621 Latest Revision: 20210621

20231215

PMC7236069

10.1111/bph.15007

32022249