Silencing IQGAP1 alleviates hepatic fibrogenesis via blocking bone marrow mesenchymal stromal cell recruitment to fibrotic liver

Abstract

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 S1Pinduced 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)-dietinduced 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 IQ-GAP1 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 (S1PR 3 ) 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.

Role of IQ Motif-Containing GTPase-Activating Proteins in Hepatocellular Carcinoma

“…These findings suggest the putative role of IQGAP1 in liver inflammation and fibrogenesis ( 85 ). The increased levels of IQGAP1 in fibrotic liver were also confirmed by Ma and colleagues, who further demonstrated the cell type fraction responsible for such increase ( 79 ). IQGAP1 expression was found to be remarkably elevated in non-parenchymal cells and myofibroblasts during murine liver fibrosis ( 79 ).…”

“…The increased levels of IQGAP1 in fibrotic liver were also confirmed by Ma and colleagues, who further demonstrated the cell type fraction responsible for such increase ( 79 ). IQGAP1 expression was found to be remarkably elevated in non-parenchymal cells and myofibroblasts during murine liver fibrosis ( 79 ). Sphingosine 1-phosphate (S1P) mediated bone marrow mesenchymal stromal cells (BMSCs) migration from bone marrow to the injured liver is one of the primary sources of myofibroblasts ( 86 ).…”

“…Sphingosine 1-phosphate (S1P) mediated bone marrow mesenchymal stromal cells (BMSCs) migration from bone marrow to the injured liver is one of the primary sources of myofibroblasts ( 86 ). Likewise, Ma and colleagues showed that IQGAP1 mediated SIP-induced BMSC migration and motility ( 79 , 86 ). S1P induces membrane translocation of IQGAP1 and promotes the interaction between IQGAP1 and Cdc42/Rac1 to facilitate BMSC migration to the liver.…”

“…Likewise, role of IQGAPs has been quite extensively explored in various cancers including HCC. However, the investigations for the implications of IQGAPs in other liver diseases such as fatty liver disease, fibrosis, and cirrhosis are still too scarce and need more scientific research to explore the role and importance of these scaffold proteins in liver diseases ( 76 – 79 ).…”

“…S1P induces membrane translocation of IQGAP1 and promotes the interaction between IQGAP1 and Cdc42/Rac1 to facilitate BMSC migration to the liver. Moreover, the knockdown of IQGAP1 significantly reduced cell viability and migratory capacity in BMSC cells ( 79 ).…”