Therapeutic potential of a synthetic FABP4 inhibitor 8g on atherosclerosis in ApoE-deficient mice: the inhibition of lipid accumulation and inflammation

Abstract

Fatty-acid-binding proteins are small (14–15 kDa) proteins that bind reversibly with high affinity to hydrophobic ligands. Fatty-acid-binding protein 4 (FABP4), highly expressed in adipocytes and macrophages, plays an essential regulatory role in energy metabolism and inflammation. In a previous study, we reported N-(2-(4-(1-allyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo(3,2-d)pyrimidin-6-yl)phenoxy)ethyl)picolinamide (8g), as an effective agent to prevent non-alcoholic fatty liver disease (NAFLD). In the present study, we found 8g to be a novel FABP4 inhibitor that significantly inhibited triglyceride accumulation and the expression of Fabp4 in 3T3-L1 adipocytes. In macrophages, 8g inhibited both Fabp4 and pro-inflammatory cytokine production. Importantly, in a co-culture system of adipocytes and macrophages, which mimics the functional interaction between adipocytes and macrophages within adipose tissue, 8g inhibited the expression of Fabp4 and cytokine production, and downregulated FABP4 and stress kinases. In line with the in vitro results, 8g markedly and dose-dependently decreased the expression of serum FABP4 and atherosclerotic lesion area in apolipoprotein E-deficient (ApoE-deficient) mice, and significantly reduced epididymal fat mass and plasma levels of triglycerides in diet-induced obesity (DIO) mice. All together, 8g is a novel FABP4 inhibitor demonstrated to ameliorate atherosclerosis through the reduction of lipid accumulation and inflammatory response, which may offer a potent therapeutic strategy against atherosclerosis and obesity.