Chuan Wang1, Kazutoshi Nishijima1, Shuji Kitajima1, Manabu Niimi1, Haizhao Yan1, Yajie Chen1, Bo Ning1, Fumikazu Matsuhisa1, Enqi Liu1, Jifeng Zhang1, Y Eugene Chen1, Jianglin Fan2. 1. From the Department of Molecular Pathology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, Graduate School, University of Yamanashi, Japan (C.W., M.N., B.N., H.Y., Y.C., J.F.); Department of Pathology, Xi'an Medical University, China (B.N., J.F.); Animal Research Laboratory, Bioscience Education-Research Support Center, Akita University, Japan (K.N.); Analytical Research Center for Experimental Sciences, Saga University, Japan (S.K., F.M.); Research Institute of Atherosclerotic Disease and Laboratory Animal Center, Xi'an Jiaotong University School of Medicine, China (E.L.); and Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor (J.Z., Y.E.C.). 2. From the Department of Molecular Pathology, Faculty of Medicine, Graduate Faculty of Interdisciplinary Research, Graduate School, University of Yamanashi, Japan (C.W., M.N., B.N., H.Y., Y.C., J.F.); Department of Pathology, Xi'an Medical University, China (B.N., J.F.); Animal Research Laboratory, Bioscience Education-Research Support Center, Akita University, Japan (K.N.); Analytical Research Center for Experimental Sciences, Saga University, Japan (S.K., F.M.); Research Institute of Atherosclerotic Disease and Laboratory Animal Center, Xi'an Jiaotong University School of Medicine, China (E.L.); and Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor (J.Z., Y.E.C.). jianglin@yamanashi.ac.jp.
Abstract
OBJECTIVE: Endothelial lipase (EL) is a key determinant in plasma high-density lipoprotein-cholesterol. However, functional roles of EL on the development of atherosclerosis have not been clarified. We investigated whether hepatic expression of EL affects plasma lipoprotein metabolism and cholesterol diet-induced atherosclerosis. APPROACH AND RESULTS: We generated transgenic (Tg) rabbits expressing the human EL gene in the liver and then examined the effects of EL expression on plasma lipids and lipoproteins and compared the susceptibility of Tg rabbits with cholesterol diet-induced atherosclerosis with non-Tg littermates. On a chow diet, hepatic expression of human EL in Tg rabbits led to remarkable reductions in plasma levels of total cholesterol, phospholipids, and high-density lipoprotein-cholesterol compared with non-Tg controls. On a cholesterol-rich diet for 16 weeks, Tg rabbits exhibited significantly lower hypercholesterolemia and less atherosclerosis than non-Tg littermates. In Tg rabbits, gross lesion area of aortic atherosclerosis was reduced by 52%, and the lesions were characterized by fewer macrophages and smooth muscle cells compared with non-Tg littermates. CONCLUSIONS: Increased hepatic expression of EL attenuates cholesterol diet-induced hypercholesterolemia and protects against atherosclerosis.
OBJECTIVE:Endothelial lipase (EL) is a key determinant in plasma high-density lipoprotein-cholesterol. However, functional roles of EL on the development of atherosclerosis have not been clarified. We investigated whether hepatic expression of EL affects plasma lipoprotein metabolism and cholesterol diet-induced atherosclerosis. APPROACH AND RESULTS: We generated transgenic (Tg) rabbits expressing the humanEL gene in the liver and then examined the effects of EL expression on plasma lipids and lipoproteins and compared the susceptibility of Tgrabbits with cholesterol diet-induced atherosclerosis with non-Tg littermates. On a chow diet, hepatic expression of humanEL in Tgrabbits led to remarkable reductions in plasma levels of total cholesterol, phospholipids, and high-density lipoprotein-cholesterol compared with non-Tg controls. On a cholesterol-rich diet for 16 weeks, Tgrabbits exhibited significantly lower hypercholesterolemia and less atherosclerosis than non-Tg littermates. In Tgrabbits, gross lesion area of aortic atherosclerosis was reduced by 52%, and the lesions were characterized by fewer macrophages and smooth muscle cells compared with non-Tg littermates. CONCLUSIONS: Increased hepatic expression of EL attenuates cholesterol diet-induced hypercholesterolemia and protects against atherosclerosis.
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