A high level of circulating
free fatty acids (FFAs) is known to be an important trigger for macrophage apoptosis during the development of
atherosclerosis. However, the underlying mechanism by which FFAs result in macrophage apoptosis is not well understood. In cultured human macrophage Thp-1 cells, we showed that
palmitate (PA), the most abundant FFA in circulation, induced excessive reactive oxidative substance production, increased
malondialdehyde concentration, and decreased
adenosine triphosphate levels. Furthermore, PA treatment also led to
mitochondrial dysfunction, including the decrease of mitochondrial number, the impairment of respiratory complex IV and
succinate dehydrogenase activity, and the reduction of mitochondrial membrane potential. Mitochondrial apoptosis was also detected after PA treatment, indicated by a decrease in
cytochrome c release, downregulation of Bcl-2, upregulation of Bax, and increased
caspase-3 activity. PA treatment upregulated the expression of adipocyte
fatty acid-binding protein (A-FABP), a critical regulator of
fatty acid trafficking and lipid metabolism. Inhibition of A-FABP with
BMS309403, a small-molecule A-FABP inhibitor, almost reversed all of these indexes. Thus, this study suggested that PA-mediated macrophage apoptosis through A-FABP upregulation, which subsequently resulted in
mitochondrial dysfunction and reactive oxidative stress. Inhibition of A-FABP may be a potential therapeutic target for macrophage apoptosis and to delay the progress of
atherosclerosis.