IQ motif-containing guanosine triphosphatase (GTPase)-activating protein 1 (IQGAP1) is a cytosolic scaffolding protein involved in cell migration. Our previous studies suggest sphingosine 1-phosphate (S1P) triggers bone marrow (BM) mesenchymal stromal cells (BMSCs) to damaged liver, thereby promoting liver fibrosis. However, the role of IQGAP1 in S1P-induced BMSC migration and liver fibrogenesis remains unclear. Chimeric mice of BM cell labeled by EGFP were used to build methionine-choline-deficient and high-fat (MCDHF)-diet-induced mouse liver fibrosis. IQGAP1 small interfering RNA (siRNA) was utilized to silence IQGAP1 in vivo. IQGAP1 expression is significantly elevated in MCDHF-diet-induced mouse fibrotic livers. Positive correlations are presented between IQGAP1 and fibrosis hallmarks expressions in human and mouse fibrotic livers. In vitro, depressing IQGAP1 expression blocks S1P-induced motility and cytoskeleton remodeling of BMSCs. S1P facilitates IQGAP1 aggregating to plasma membrane via S1P receptor 3 (S1PR3) and Cdc42/Rac1. In addition, IQGAP1 binds to Cdc42/Rac1, regulating S1P-induced activation of Cdc42/Rac1 and mediating BMSC migration in concert. In vivo, silencing IQGAP1 reduces the recruitment of BMSCs to impaired liver and effectively alleviates liver fibrosis induced by MCDHF diet. Together, silencing IQGAP1 relieves liver fibrosis by blocking BMSC migration, providing an effective therapeutic strategy for liver fibrosis.

Here microRNAs (miRNAs) with potentially therapeutic effects were screened and explored during liver fibrogenesis and angiogenesis via targeting the important mediators. Chimera mice with EGFP+ bone marrow mesenchymal stromal cells (BMSCs) were fed with methionine-choline-deficient and high-fat (MCDHF) diet to induce liver injury. Increased expression of platelet-derived growth factor receptor-beta (PDGFR-β) was detected in MCDHF mice, with a positive correlation to fibrosis and angiogenesis markers. BMSCs contributed to the significant proportion of PDGFR-β+ cells in the fibrotic liver. MicroRNA-26b-5p (miR-26b-5p) was predicted to target PDGFR-β from three databases. The hepatic expression of miR-26b-5p was decreased in the fibrotic liver, with a negative correlation to PDGFR-β and fibrosis and angiogenesis markers. miR-26b-5p directly targeted PDGFR-β in TGF-β1-treated BMSCs by pull-down and lucifer reporter assays, which can be sponged by long non-coding RNA (lncRNA) maternally expressed gene 3 (lncMEG3). Microarray analysis revealed that miR-26b-5p overexpression affected a list of genes associated with fibrosis and angiogenesis. In vivo miR-26b-5p negatively regulated PDGFR-β expression and attenuated liver fibrosis and angiogenesis. Together, miR-26b-5p inhibits liver fibrogenesis and angiogenesis via directly targeting PDGFR-β and interacting with lncMEG3, which may represent an effective therapeutic strategy for liver fibrosis.

目的预测、筛选并探究是否存在特定的microRNA能够影响人肝脏星形细胞LX-2中鞘胺醇激酶1（sphingosine kinase1,SphK1） mRNA的表达。方法采用生物信息学数据库预测microRNA,采用实时荧光定量聚合酶链式反应（real-time quantitative polymerase chain reaction,RT-qPCR）检测SphK1 mRNA的表达。结果预测筛选出的miR-378a-5p、miR-92a-2-5p和miR-708-5p中,只有miR-378a-5p能够抑制LX-2中由转化生长因子β1 （transforming growth factor-β1,TGF-β1）介导的SphK1 mRNA表达上调这一过程。而在LX-2中转染miR-378a-5p的抑制剂阻断其作用后,SphK1 mRNA的表达上调。结论 miR-378a-5p参与LX-2中Sph K1 mRNA表达的调控,并且能够抑制由TGF-β1介导的SphK1 mRNA表达上调。