Canna~Fangled Abstracts

CB2R agonist GW405833 alleviates acute liver failure in mice via inhibiting HIF-1α-mediated reprogramming of glycometabolism and macrophage proliferation

By January 25, 2023January 26th, 2023No Comments

doi: 10.1038/s41401-022-01037-8.

Online ahead of print.


The inflammatory responses involving infiltration and activation of liver macrophages play a vital role in acute liver failure (ALF). In the liver of ALF mice, cannabinoid receptor 2 (CB2R) is significantly upregulated on macrophages, while CB2R agonist GW405833 (GW) could protect against cell death in acute liver damage. In this study, we investigated the molecular mechanisms underlying the protective effects of GW against ALF in vivo and in vitro from a perspective of macrophage glycometabolism. Mice were pretreated with GW (10 mg/kg, i.p.), then were injected with D-GalN (750 mg/kg, i.p.) and LPS (10 mg/kg, i.p.) to induce ALF. We verified the protective effects of GW pretreatment in ALF mice. Furthermore, GW pretreatment significantly reduced liver macrophage infiltration and M1 polarization, and inhibited the release of inflammatory factors TNF-α and IL-1β in ALF mice. These protective effects were eliminated by CB2R antagonist SR144528 or in CB2R-/- ALF mice. We used LPS-stimulated RAW264.7 cells as an in vitro M1 macrophage-centered model of inflammatory response, and demonstrated that pretreatment with GW (10 μM) significantly reduced glucose metabolism by inhibiting glycolysis, which inhibited LPS-induced macrophage proliferation and inflammatory cytokines release. We verified these results in a stable CB2R-/- RAW264.7 cell line. Moreover, we found that GW significantly inhibited the expression of hypoxia inducible factor 1α (HIF-1α). Using a stable HIF-1α-/- RAW264.7 cell line, we confirmed that GW reduced the release of inflammatory cytokines from macrophages and inhibited glycolysis by downregulating HIF-1α expression. In conclusion, activation of CB2Rs inhibits the proliferation of hepatic macrophages and release of inflammatory factors in ALF mice through downregulating HIF-1α to inhibit glycolysis.

Keywords: GW405833, RAW264.7 cells, SR144528, acute liver failure, cannabinoid receptor 2, glycolysis, hypoxia-inducible factor 1α, macrophages


    1. Louvet A, Teixeira-Clerc F, Chobert MN, Deveaux V, Pavoine C, Zimmer A, et al. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology. 2011;54:1217–26. – DOI
    1. Chen J, Huang ZB, Li H, Zheng X, Chen JJ, Wang XB, et al. Early diagnostic biomarkers of sepsis for patients with acute-on-chronic liver failure: a multicenter study. Infect Dis Ther. 2021;10:281–90. – DOI
    1. Chen J, Huang ZB, Fan XG, Hu XW, Qi M, Liao CJ, et al. Potential predictors for prognosis and postpartum recovery time of acute fatty liver of pregnancy. BMC Pregnancy Childbirth. 2020;20:601. – DOI
    1. Olah A, Szekanecz Z, Biro T. Targeting cannabinoid signaling in the immune system: “High”-ly exciting questions, possibilities, and challenges. Front Immunol. 2017;8:1487. – DOI
    1. Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017;17:306–21. – DOI

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