Novel Roles of FFAR4 in Macrophage Foam Cell Formation

Abstract

Free fatty acid receptor 4 (FFAR4), also known as G‐protein coupled receptor 120 (GPR120), is a long‐chain unsaturated fatty acid receptor expressed in adipocytes, endothelial cells, and macrophages. Activation of FFAR4 helps maintain metabolic homeostasis by regulating adipogenesis, insulin sensitivity, and inflammation. While FFAR4 is best known for its role its role in preventing obesity and diabetes, recent studies have demonstrated that FFAR4 may also play an important role in the development of atherosclerosis and cardiovascular disease (CVD). Given FFAR4’s importance in anti‐inflammatory signaling and high expression levels in macrophages, we designed experiments to test the hypothesis that FFAR4 prevents the development of atherosclerosis by reversing macrophage foam cell formation, a hallmark of early atherogenesis. In these studies, we isolated peritoneal macrophages from wild‐type C57/BL6J mice and incubated them with oxidized low‐density lipoprotein (oxLDL) to generate foam cells. We then investigated the effects of FFAR4 activation by GW9508 (a synthetic agonist) on lipid accumulation, cytokine secretion, and cholesterol efflux. Activation of FFAR4 by GW9508 decreased macrophage secretion of pro‐inflammatory cytokines. We also found that activation of FFAR4 with GW9508 reduced lipid accumulation in macrophages as observed by decreased Oil Red O staining and reduced cellular cholesterol content. Additionally, activation of FFAR4 by GW9508 increased [3H]‐cholesterol efflux to high‐density lipoprotein (HDL). Interestingly, the increased efflux was accompanied by decreased scavenger receptor CD36 expression (that mediates oxLDL uptake) and increased expression of ATP binding cassette transporters, ABCA1 and ABCG1 (that mediate cholesterol efflux). Taken together, our results support an exciting and novel role for FFAR4 in the reversal of foam cell formation and could emerge this receptor as a new target for treating CVD by preventing accumulation of atherosclerotic plaque.