Adipose Fatty Acid Binding Protein Promotes Saturated Fatty Acid-induced Cell Death through Ceramide Production in Macrophages

Abstract

Abstract Macrophages play a critical role in obesity-associated chronic inflammation and disorders. However, the molecular mechanisms of how macrophages respond to elevated fatty acids (FAs) and contribute to sterile inflammation in obesity remain to be fully elucidated. Here, we report a new mechanism by which dietary FAs, in particular saturated FAs, were able to directly trigger macrophage cell death. We demonstrated that excess saturated FAs, but not unsaturated FAs, induced the production of cytotoxic ceramides in macrophages. Most importantly, expression of adipose fatty acid binding protein (A-FABP) in macrophages facilitated metabolism of excess saturated FAs for ceramide synthesis. Inhibition or deficiency of A-FABP in macrophages decreased saturated FA-induced ceramide production, thereby resulting in reduced cell death. Furthermore, A-FABP-deficient obese mice exhibited increased percentage of CD36+ macrophages in peripheral as compared to WT control mice. Altogether, our data suggest that excess saturated FAs in diets serve as new triggers in inducing ceramide production and macrophage cell death through elevated expression of A-FABP, thus contributing to sterile inflammation in obesity.