Butyrate has been recently identified as a natural ligand of the G-protein-coupled receptor 41 （GPR41）. In addition, it is an inhibitor of histone deacetylase （HDAC）. Butyrate treatment results in the hyperacetyla...Butyrate has been recently identified as a natural ligand of the G-protein-coupled receptor 41 （GPR41）. In addition, it is an inhibitor of histone deacetylase （HDAC）. Butyrate treatment results in the hyperacetylation of histones, with resultant multiple biological effects including inhibition of proliferation, induction of cell cycle arrest, and apoptosis, in a variety of cultured mammalian cells. However, it is not clear whether GPR41 is actively involved in the above-mentioned processes. In this study, we generated a stable cell line expressing the hGPR41 receptor in order to investigate the involvement of GPR41 on butyrate-induced biochemical and physiologic processes. We found that GPR41 activation may be a compensatory mechanism to counter the increase in histone H3 acetylation levels induced by butyrate treatment. Moreover, GPR41 had an inhibitory effect on the anti-proliferative, pro-apoptotic effects of butyrate. GPR41 expression induced cell cycle arrest at the Gl-stage, while its activation by butyrate can cause more cells to pass the G1 checkpoint. These results indicated that GPR41 was associated with histone acetylation and might be involved in the acetylation-related regulation of cell processes including proliferation, apoptosis, and the cell cycle.展开更多
Gut microbiota-derived propionate has been shown to ameliorate alcoholic liver disease(ALD)through modulating gut-liver axis in our previous study.However,the underlying mechanism remains unclear.In this study,we synt...Gut microbiota-derived propionate has been shown to ameliorate alcoholic liver disease(ALD)through modulating gut-liver axis in our previous study.However,the underlying mechanism remains unclear.In this study,we synthesized propionylated high-amylose maize starch(HAMSP)to achieve gut-targeted delivery of propionate,evaluated its therapeutical potential against ALD compared with oral sodium propionate,and elucidated its mechanism targeting the gut-liver axis.Animal experiments demonstrated that HAMSP outperformed oral sodium propionate in improving liver function,attenuating liver steatosis,reducing liver oxidative stress and inflammation in ALD mice.Mechanistic investigations revealed that depletion of propionate receptors GPR41 and GPR43 blocked the protective effects of HAMSP against ALD.In ALD mice,the activation of GPR41/43 triggered by HAMSP stimulated IL-22 production,leading to STAT3 phosphorylation,which enhanced the gut barrier integrity and suppressed LPS translocation,thereby restoring the gut-liver axis homeostasis.These findings were further corroborated in Caco-2 cells.In summary,this study provided novel evidence that propionate regulates gut-liver axis homeostasis in ALD via the GPR41/43-IL-22-STAT3 signaling pathway.It also establishes scientific foundation for the therapeutic application of HAMSP,a gut-targeted propionate delivery agent,in ALD prevention and treatment.展开更多
AIM： To investigate the effect of short-chain fatty acids （SCFAs） on production of prostaglandin E2 （PGE2）, cytokines and chemokines in human monocytes. METHODS： Human neutrophils and monocytes were isolated fro...AIM： To investigate the effect of short-chain fatty acids （SCFAs） on production of prostaglandin E2 （PGE2）, cytokines and chemokines in human monocytes. METHODS： Human neutrophils and monocytes were isolated from human whole blood by using 1-Step Polymorph and RosetteSep Human Monocyte Enrichment Cocktail, respectively. Human GPR41 and GPR43 mRNA expression was examined by quantitative realtime polymerase chain reaction, The calcium flux assay was used to examine the biological activities of SCFAs in human neutrophils and monocytes. The effect of SCFAs on human monocytes and peripheral blood mononuclear cells （PBMC） was studied by measuring PGE2, cytokines and chemokines in the supernatant. The effect of SCFAs in vivo was examined by intraplantar injection into rat paws. RESULTS： Human GPR43 is highly expressed in human neutrophils and monocytes. SCFAs induce robust calcium flux in human neutrophils, but not in human monocytes. In this study, we show that SCFAs can induce human monocyte release of PGE2 and that this effect can be enhanced in the presence of lipopolysaccharide （LPS）. In addition, we demonstrate that PGE2 production induced by SCFA was inhibited by pertussis toxin, suggesting the involvement of a receptor-mediated mechanism. Furthermore, SCFAs can specifically inhibit constitutive monocyte chemotactic protein-1 （MCP-1） production and LPS-induced interleukin-10 （IL-10） production in human monocytes without affecting the secretion of other cytokines and chemokines examined. Similar activities were observed in human PBMC for the release of PGE2, MCP-1 and IL-10 after 5CFA treatment. In addition, SCFAs inhibit LPS-induced production of tumor necrosis factor-α and interferon-7 in human PBIVlC. Finally, we show that SCFAs and LPS can induce PGE2 production in vivo by intraplantar injection into rat paws （P 〈 0.01）. CONCLUSION： SCFAs can have distinct antiinflammatory activities due to their regulation of PGE2, cytokine and chemokine release from human immune cells.展开更多
基金supported by the grant from the National High-tech R&D Program(863 Program)(No.2007AA02Z163)the National Natural Science Foundation of China(No. 31000574)the Fundamental Research Fund for the Central Universities(No.78210042)
文摘Butyrate has been recently identified as a natural ligand of the G-protein-coupled receptor 41 （GPR41）. In addition, it is an inhibitor of histone deacetylase （HDAC）. Butyrate treatment results in the hyperacetylation of histones, with resultant multiple biological effects including inhibition of proliferation, induction of cell cycle arrest, and apoptosis, in a variety of cultured mammalian cells. However, it is not clear whether GPR41 is actively involved in the above-mentioned processes. In this study, we generated a stable cell line expressing the hGPR41 receptor in order to investigate the involvement of GPR41 on butyrate-induced biochemical and physiologic processes. We found that GPR41 activation may be a compensatory mechanism to counter the increase in histone H3 acetylation levels induced by butyrate treatment. Moreover, GPR41 had an inhibitory effect on the anti-proliferative, pro-apoptotic effects of butyrate. GPR41 expression induced cell cycle arrest at the Gl-stage, while its activation by butyrate can cause more cells to pass the G1 checkpoint. These results indicated that GPR41 was associated with histone acetylation and might be involved in the acetylation-related regulation of cell processes including proliferation, apoptosis, and the cell cycle.
基金supported by the Shandong Provincial Natural Science Foundation(Grant No.ZR2022QH051)the National Natural Science Foundation of China(Grant No.82204325,82304430 and 82404568)Science,Education and Industry Integration Innovation Pilot Project from Qilu University of Technology(Grant No.2025YSZX01).
文摘Gut microbiota-derived propionate has been shown to ameliorate alcoholic liver disease(ALD)through modulating gut-liver axis in our previous study.However,the underlying mechanism remains unclear.In this study,we synthesized propionylated high-amylose maize starch(HAMSP)to achieve gut-targeted delivery of propionate,evaluated its therapeutical potential against ALD compared with oral sodium propionate,and elucidated its mechanism targeting the gut-liver axis.Animal experiments demonstrated that HAMSP outperformed oral sodium propionate in improving liver function,attenuating liver steatosis,reducing liver oxidative stress and inflammation in ALD mice.Mechanistic investigations revealed that depletion of propionate receptors GPR41 and GPR43 blocked the protective effects of HAMSP against ALD.In ALD mice,the activation of GPR41/43 triggered by HAMSP stimulated IL-22 production,leading to STAT3 phosphorylation,which enhanced the gut barrier integrity and suppressed LPS translocation,thereby restoring the gut-liver axis homeostasis.These findings were further corroborated in Caco-2 cells.In summary,this study provided novel evidence that propionate regulates gut-liver axis homeostasis in ALD via the GPR41/43-IL-22-STAT3 signaling pathway.It also establishes scientific foundation for the therapeutic application of HAMSP,a gut-targeted propionate delivery agent,in ALD prevention and treatment.
文摘AIM： To investigate the effect of short-chain fatty acids （SCFAs） on production of prostaglandin E2 （PGE2）, cytokines and chemokines in human monocytes. METHODS： Human neutrophils and monocytes were isolated from human whole blood by using 1-Step Polymorph and RosetteSep Human Monocyte Enrichment Cocktail, respectively. Human GPR41 and GPR43 mRNA expression was examined by quantitative realtime polymerase chain reaction, The calcium flux assay was used to examine the biological activities of SCFAs in human neutrophils and monocytes. The effect of SCFAs on human monocytes and peripheral blood mononuclear cells （PBMC） was studied by measuring PGE2, cytokines and chemokines in the supernatant. The effect of SCFAs in vivo was examined by intraplantar injection into rat paws. RESULTS： Human GPR43 is highly expressed in human neutrophils and monocytes. SCFAs induce robust calcium flux in human neutrophils, but not in human monocytes. In this study, we show that SCFAs can induce human monocyte release of PGE2 and that this effect can be enhanced in the presence of lipopolysaccharide （LPS）. In addition, we demonstrate that PGE2 production induced by SCFA was inhibited by pertussis toxin, suggesting the involvement of a receptor-mediated mechanism. Furthermore, SCFAs can specifically inhibit constitutive monocyte chemotactic protein-1 （MCP-1） production and LPS-induced interleukin-10 （IL-10） production in human monocytes without affecting the secretion of other cytokines and chemokines examined. Similar activities were observed in human PBMC for the release of PGE2, MCP-1 and IL-10 after 5CFA treatment. In addition, SCFAs inhibit LPS-induced production of tumor necrosis factor-α and interferon-7 in human PBIVlC. Finally, we show that SCFAs and LPS can induce PGE2 production in vivo by intraplantar injection into rat paws （P 〈 0.01）. CONCLUSION： SCFAs can have distinct antiinflammatory activities due to their regulation of PGE2, cytokine and chemokine release from human immune cells.
