AIM:To examine the effect of farnesoid X receptor(FXR)activation by GW4064 on endotoxin-induced hepatic inflammation in nonalcoholic fatty liver disease(NAFLD)and the underlying mechanism.METHODS:Six-week-old male C57...AIM:To examine the effect of farnesoid X receptor(FXR)activation by GW4064 on endotoxin-induced hepatic inflammation in nonalcoholic fatty liver disease(NAFLD)and the underlying mechanism.METHODS:Six-week-old male C57BL/6 mice were fed a normal diet or a high-fat(HF)diet for 8 wk.HF dietfed mice were intraperitoneally injected with GW4064(30 mg/kg)or DMSO(vehicle)once daily for a week and then sacrificed after lipopolysaccharide(LPS,50μg/mouse)administration.Hepatic inflammation,levels of the macrophage marker F4/80,and apoptosis were measured at the end of the study.Additionally,the expression of proinflammatory genes involved in NAFLD(interleukin-6,interleukin-1β,interferon-γ,MCP-1)were analyzed by real-time PCR in the murine macrophagecell line RAW 264.7 cultured with or without GW4064(2μmol/L)before treatment with LPS.RESULTS:In patients with NAFLD,the expression of FXR was detected by immunohistochemical staining and the relation between FXR expression and NAFLD activity score(NAS)was analyzed.Activation of FXR by GW4064 alleviated hepatic inflammation induced by endotoxin in a murine NAFLD model fed an HF diet as reflected by reduced serum levels of aspartate aminotransferase and alanine aminotransferase.Apoptosis and proinflammatory cytokine levels in liver tissues were also reduced by GW4064,and GW4064 could reduce induction of proinflammatory cytokines by LPS in vitro.FXR levels were reduced in patients with nonalcoholic steatohepatitis compared with healthy controls and were negatively correlated with NAS.CONCLUSION:FXR activation attenuates LPS-induced hepatic inflammation in murine NAFLD by reducing expression of proinflammatory cytokines in macrophages.展开更多
文摘AIM:To examine the effect of farnesoid X receptor(FXR)activation by GW4064 on endotoxin-induced hepatic inflammation in nonalcoholic fatty liver disease(NAFLD)and the underlying mechanism.METHODS:Six-week-old male C57BL/6 mice were fed a normal diet or a high-fat(HF)diet for 8 wk.HF dietfed mice were intraperitoneally injected with GW4064(30 mg/kg)or DMSO(vehicle)once daily for a week and then sacrificed after lipopolysaccharide(LPS,50μg/mouse)administration.Hepatic inflammation,levels of the macrophage marker F4/80,and apoptosis were measured at the end of the study.Additionally,the expression of proinflammatory genes involved in NAFLD(interleukin-6,interleukin-1β,interferon-γ,MCP-1)were analyzed by real-time PCR in the murine macrophagecell line RAW 264.7 cultured with or without GW4064(2μmol/L)before treatment with LPS.RESULTS:In patients with NAFLD,the expression of FXR was detected by immunohistochemical staining and the relation between FXR expression and NAFLD activity score(NAS)was analyzed.Activation of FXR by GW4064 alleviated hepatic inflammation induced by endotoxin in a murine NAFLD model fed an HF diet as reflected by reduced serum levels of aspartate aminotransferase and alanine aminotransferase.Apoptosis and proinflammatory cytokine levels in liver tissues were also reduced by GW4064,and GW4064 could reduce induction of proinflammatory cytokines by LPS in vitro.FXR levels were reduced in patients with nonalcoholic steatohepatitis compared with healthy controls and were negatively correlated with NAS.CONCLUSION:FXR activation attenuates LPS-induced hepatic inflammation in murine NAFLD by reducing expression of proinflammatory cytokines in macrophages.
基金This work was supported by the National Key Research and Development Program of China(No.2020YFC2005000)the National Natural Science Foundation of China(No.81970606 to X.Z.and No.81970595 to Y.G.)+2 种基金Education Department of Liaoning Province,China(No.507123 to Z.L.)the Dalian Young Star of Science and Technology(No.2019RQ116 to Z.L.)Liaoning BaiQianWan Talents Program.
