广东医学2026，Vol.47Issue(4)：496-507,12.DOI:10.13820/j.cnki.gdyx.20251930
维生素D及其受体上调IGF-1抑制TGF-β1/SMAD2/3信号延缓CCl4诱导肝纤维化的进展
Mechanistic study of Vitamin D/Vitamin D receptor upregulation of IGF-1 in inhibiting TGF-β1/SMAD2/3 signaling to delay CCl4-induced liver fibrosis progression in mice
摘要
Abstract
Objective To investigate the protective mechanism of the vitamin D(VD3)/vitamin D receptor(VDR)signaling axis in liver fibrosis,focusing on its ability to upregulate insulin-like growth factor-1(IGF-1)and antagonize the TGF-β1/SMAD2/3 signaling pathway.Methods Seventy male C57BL/6 mice(7-8 weeks old)were randomly assigned to seven groups:control,CCl4-induced fibrosis model,model+VD3(10 IU/kg/day orally),model+Lenti-VDR shRNA,model+Lenti-VDR shRNA+VD3,model+Lenti-shRNA NT,and model+Lenti-shRNA NT+VD3.Human hepatic stellate LX2 cells were also treated in vitro with LPS,Lenti-VDR shRNA,Lenti-VDR over-expression(OE),or controls.qPCR was used to quantify hepatic mRNA levels of VDR,IGF-1,Col1 α1,Serpine1,Timp1,and Fn1.Immunofluorescence detected Collagen Ⅰ and CD31.Western blot measured VDR,α-SMA,TGF-β1,p-SMAD2/3,NF-κB p65,p-p65,ERK1/2,and p-ERK1/2.ELISA quantified serum IGF-1,ALT,TNF-α,IL-6,and CCL2.Results Compared with controls,CCl4-treated mice showed decreased serum 1,25(OH)2D3,elevated ALT,TNF-α,IL-6,CCL2,Col1 α1,Serpine1,Timp1,Fn1,Collagen Ⅰ,CD31,TGF-β1,p-SMAD2/3,p-p65/p65,and p-ERK1/2/ERK1/2(P＜0.05).VD3 administration partially reversed these effects.VDR knockdown via Lenti-VDR shRNA aggravated fibrosis markers and signaling activation.In LX2 cells,VDR knockdown enhanced,whereas VDR overexpression reduced,LPS-induced α-SMA,TGF-β1,p-SMAD2,and p-SMAD3 lev-els(P＜0.05).Conclusion VDR knockdown exacerbates CCl4-induced liver fibrosis by inhibiting IGF-1 expres-sion,thereby activating the TGF-β1/SMAD2/3 pathway and hepatic stellate cell activation.VD3/VDR upregulation of IGF-1 represents a potential therapeutic strategy to delay liver fibrosis progression.关键词
肝纤维化/维生素D/胰岛素样生长因子-1/肝星状细胞/TGF-β1/SMAD2/3信号通路Key words
liver fibrosis/vitamin D/insulin like growth factor 1/hepatic stellate cells/TGF-β1/SMAD2/3 signaling pathway分类
医药卫生引用本文复制引用
王翠翠,李倩,范旻,姚俊英..维生素D及其受体上调IGF-1抑制TGF-β1/SMAD2/3信号延缓CCl4诱导肝纤维化的进展[J].广东医学,2026,47(4):496-507,12.基金项目
自治区卫生健康青年医学科技人才专项科研项目(WJWY-202324) （WJWY-202324）
