A Role for DPP4 Expression via Oxidized LDL/TLR4/TRIF/CD36 Pathways in Human Obesity and Atherosclerosis

Abstract Objective Dipeptidyl peptidase IV (DPP4) is well-known for its regulatory role in incretin biology. Although prior studies have suggested a role for DPP4 in atherosclerosis, the regulation of DPP4 in diabetes and atherosclerosis has not been investigated. In this study, we investigated the relationship of DPP4 with human aortic atherosclerosis and the role of obesity. Methods and Results We tested the expression of membrane bound DPP4 on circulating monocytes and plasma DPP4 activity (cleaved) in patients with atherosclerosis and their relationship with measures of metabolic health. In atherosclerosis, both cleaved and membrane bound DPP4 were increased. DPP4 expression on monocytes was positively correlated with atherosclerotic plaque volume assessed by high-resolution MRI with expression positively correlating with non-HDL cholesterol level (P=0.0242) but not fasting blood glucose or insulin. Oxidized low-density lipoprotein (oxLDL) up-regulated DPP4 expression on macrophages with a preferential increase in CD36+ cells. OxLDL mediated increase in DPP4 was abolished by siRNA-mediated Toll-like receptor 4 (TLR4) knock-down and considerably diminished by CD36 deficiency. Loss of TRIF but not MyD88 attenuated DPP4 increase with oxLDL. Conclusions DPP4 expression on monocytes correlates with atherosclerotic plaque volume with a key role for oxidized LDL in regulating DPP4 expression via CD36/TLR4/TRIF pathways. Increased DPP4 in response to oxidized lipids may represent an integrated mechanism by which post-prandial glucose metabolism is linked to lipoprotein abnormalities potentiates atherosclerosis.