Abstract
Background and Aims: Atherosclerosis is characterized by the infiltration and accumulation of monocytes in the arterial wall, combined with elevated plasma low density lipoprotein (LDL) and triglycerides, and low levels of high density lipoprotein (HDL). Apolipoprotein A-I (apoA-I), the main HDL apolipoprotein, is not only athero-protective but can also increase insulin secretion from pancreatic β-cells. Our laboratory recently demonstrated that in response to a ‘western’ diet TNF-related apoptosis-inducing ligand (TRAIL)-deficiency accelerated plaque development in ApoE-/- mice, and promoted features of diabetes typical to those observed in humans. We sought to determine whether reconstituted HDL (rHDL) could improve TRAIL-dependent disease. Methods and Results: TRAIL-/-ApoE-/- and ApoE-/- mice on a ‘western’ diet for 12 w received 3 weekly infusions of either PBS (vehicle) or rHDL (20 mg/kg apoA-I, 1-palmitoyl-2-linoleoyl phosphatidylcholine) in the final 2 weeks of feeding prior to euthanasia. While no change in weight gain was observed, administration of rHDL significantly reduced plasma cholesterol, triglyceride and glucose levels, and improved glucose clearance and insulin sensitivity in TRAIL-/-ApoE-/- mice. Notably, rHDL treatment significantly attenuated atherosclerotic plaque size in brachiocephalic arteries of TRAIL-/-ApoE-/-, but not in ApoE-/- mice. rHDL-treated TRAIL-deficient mice also displayed elevated aortic mRNA expression of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. This was associated with significantly increased expression of the pan macrophage marker F4/80 and the M2 marker CD206, suggesting that the rHDL stimulated polarization towards an M2 phenotype. Immunohistological analysis of the rHDL-treated TRAIL-/-ApoE-/- pancreata revealed increased insulin expression and reduced macrophage infiltration relative to ApoE-/- pancreata. Conclusions: This is the first demonstration of rHDL improving atherosclerosis and rescuing features of diabetes which are dependent on TRAIL. Understanding how rHDL may be beneficial in TRAIL-dependent disease could identify new strategies in the treatment of atherosclerosis and associated diabetic complications.
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