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BACKGROUND AND AIMS Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) plays a crucial role in triglyceride hydrolysis, and GPIHBP1 deficiency leads to severe hypertriglyceridemia (HTG). Gpihbp1 knockout (GKO) mice develop mild lesions in the aortic root at the age of 11 months. Herein, we investigated the effect of Gpihbp1 deficiency on atherosclerosis (AS) under diabetic conditions. METHODS For experiment 1, diabetes was induced in GKO and wild-type (WT) mice by injection of streptozotocin at 3 months of age and lasted for 4 months. For experiment 2, diabetes was induced in Gpihbp1/low-density lipoprotein receptor (Ldlr) double-knockout (GLDKO) mice, Ldlr knockout (LKO) mice were used as controls. The experiment was continued for 3 or 5 months. Plasma glucose and lipid levels were measured, and atherosclerotic lesions were analyzed at 3 and 5 months during the experiment. RESULTS No atherosclerotic lesions were detected in the aorta in GKO mice after 4 months of diabetes. Compared with LKO mice, GLDKO mice manifested enhanced aortic atherosclerotic lesions, decreased plaque stability, and increased oxidative stress and inflammation in plaques at 3 and 5 months after diabetes. Atherosclerotic lesions in the coronary artery and dilated remodeling in the aortic root were also found in GLDKO diabetic mice. CONCLUSIONS Gpihbp1 deficiency accelerates the development of AS in the aorta, and the instability of plaques in LKO mice and diabetes promotes these pathologic processes with coronary AS. These findings were probably associated with HTG caused by Gpihbp1 deficiency and with increased oxidative stress and inflammation in the atherosclerotic lesions.