FABP4 in LSECs promotes CXCL10-mediated macrophage recruitment and M1 polarization during NAFLD progression

Non-alcoholic liver disease (NAFLD) is emerging as the leading cause of end-stage liver disease with a serious threat to global health burden. Fatty acid-binding protein 4 (FABP4) is closely associated with metabolic syndromes . We aimed to explore the potential mechanisms of FABP4 in NAFLD progression . For NAFLD mice, animals were fed with high fat diet (HFD) for 20 weeks. The assays of hematoxylin and eosin , Sirius Red, oil red O staining and immunohistology were performed to evaluate hepatic pathology . Flow cytometric analysis was used to distinguish macrophage subtypes. Serum FABP4 level was positively correlate with the severity of hepatic steatosis in NAFLD patients. FABP4 expression was mainly distributed in liver sinusoidal endothelial cells (LSECs), which was significantly increased in HFD mice. The level of CXCL10 was positively correlated with FABP4 at mRNA and serum level . FABP4 inhibition resulted in decreased expression of CXCL10 . The percentage of M1 macrophage and CXCR3 + cells in infiltrated macrophage was increased in liver of HFD mice. Inhibition of FABP4 ameliorated HFD-induced M1 macrophage polarization as well as CXCR3 + macrophages recruitment. Recombinant CXCL10 and co-culturing with TMNK-1 stimulated macrophage toward M1 polarization, which could be reversed by CXCR3 inhibitor. Palmitic acid treatment resulted in increased nuclear P65 expression, which could be reversed by inhibiting FABP4. Cxcl10 expression was dramatically suppressed by NF-κB inhibitor. FABP4 in LSECs may play a pathogenic role in NAFLD course by promoting CXCL10-mediated macrophage M1 polarization and CXCR3 + macrophage infiltration via activating NF-κB/p65 signaling. A mechanistic graph of FABP4 in the regulation of NAFLD. Lipid accumulation results in lipid metabolism disorder in LSECs, together with FABP4 upregulation. FABP4 then promotes NF-κB/P65 translocation from cytoplasm to nucleus, which leads to the increase expression of CXCL10 at transcript level. LSECs-secreted CXCL10 contributes to recruitment of CXCR3 positive macrophage and M1 polarization, which ultimately exacerbating NAFLD progression . • Expression of FABP4 is upregulated during NAFLD progression, while FABP4 inhibition in LSECs alleviates liver injury. • FABP4 regulates CXCL10 secretion from LSECs and promotes the shift of LSECs toward an inflammatory phenotype. • CXCL10 promotes macrophage differentiation toward to M1 type and recruits CXCR3-positive macrophages. • Our findings suggest that FABP4 has the potential to be a new target for the treatment of NAFLD.