PREX1 depletion ameliorates high-fat diet-induced non-alcoholic fatty liver disease in mice and mitigates palmitic acid-induced hepatocellular injury via suppressing the NF-κB signaling pathway.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver diseases worldwide. Oxidative stress has been considered a key factor in the pathogenesis of NAFLD. Phosphatidylinositol (3,4,5)-trisphosphate-dependent Rac exchanger 1 (PREX1), a guanine nucleotide exchange factor for Rac, has been associated with inflammation and oxidative stress. This study aimed to investigate the biological function of PREX1 in the progression of NAFLD. Male C57BL/6 mice were fed a high-fat diet for 12 weeks to induce NAFLD in vivo. Adeno-associated virus type 8-mediated liver-specific PREX1 depletion was employed to investigate the role of PREX1 in the progression of high-fat diet-induced NAFLD. Murine hepatocyte cell line AML-12 was stimulated with palmitic acid for 24 h to induce steatosis in vitro. PREX1 depletion was carried out by transfection with PREX1 small interfering RNA. Results showed that PREX1 depletion exerted protective effects against lipid accumulation, oxidative stress and inflammation and inhibited activation of the nuclear factor-κB (NF-κB) signaling pathway in vivo and in vitro. Subsequently, NF-κB inhibitor BAY11-7082 was applied to investigate the role of the NF-κB signaling pathway in the protective effect of PREX1 inhibition against NAFLD. We confirmed that PREX1 inhibition mitigated palmitic acid-induced hepatocellular inflammation mainly via the NF-κB signaling pathway and lipid accumulation and oxidative stress at least partly via the NF-κB signaling pathway. This study highlights the biological function of PREX1 in the pathogenesis of NAFLD.