Yuanli Chen1, Yajun Duan1, Xiaoxiao Yang1, Lei Sun1, Mengyang Liu1, Qixue Wang1, Xingzhe Ma1, Wenwen Zhang1, Xiaoju Li1, Wenquan Hu1, Robert Q Miao1, Rong Xiang1, David P Hajjar1, Jihong Han2. 1. From the State Key Laboratory of Medicinal Chemical Biology (Y.C., Y.D., J.H.), Collaborative Innovation Center of Biotherapy (Y.C., Y.D., R.X., J.H.), College of Life Sciences (Y.D., X.Y., L.S., M.L., Q.W., X.M., W.Z., X.L., J.H.), Nankai University, Tianjin, China; Department of Surgery, Medical College of Wisconsin, Milwaukee (W.H., R.Q.M.); and Department of Pathology, Weill Medical College of Cornell University, New York, NY (D.P.H.). 2. From the State Key Laboratory of Medicinal Chemical Biology (Y.C., Y.D., J.H.), Collaborative Innovation Center of Biotherapy (Y.C., Y.D., R.X., J.H.), College of Life Sciences (Y.D., X.Y., L.S., M.L., Q.W., X.M., W.Z., X.L., J.H.), Nankai University, Tianjin, China; Department of Surgery, Medical College of Wisconsin, Milwaukee (W.H., R.Q.M.); and Department of Pathology, Weill Medical College of Cornell University, New York, NY (D.P.H.). jihonghan2008@nankai.edu.cn.
Abstract
OBJECTIVE: Activation of liver X receptor (LXR) inhibits atherosclerosis but induces hypertriglyceridemia. In vitro, it has been shown that mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor synergizes LXR ligand-induced macrophage ABCA1 expression and cholesterol efflux. In this study, we determined whether MEK1/2 (U0126) and LXR ligand (T0901317) can have a synergistic effect on the reduction of atherosclerosis while eliminating LXR ligand-induced fatty livers and hypertriglyceridemia. We also set out to identify the cellular mechanisms of the actions. APPROACH AND RESULTS: Wild-type mice were used to determine the effect of U0126 on a high-fat diet or high-fat diet plus T0901317-induced transient dyslipidemia and liver injury. ApoE deficient (apoE(-/-)) mice or mice with advanced lesions were used to determine the effect of the combination of T0901317 and U0126 on atherosclerosis and hypertriglyceridemia. We found that U0126 protected animals against T0901317-induced transient or long-term hepatic lipid accumulation, liver injury, and hypertriglyceridemia. Meanwhile, the combination of T0901317 and U0126 inhibited the development of atherosclerosis in a synergistic manner and reduced advanced lesions. Mechanistically, in addition to synergistic induction of macrophage ABCA1 expression, the combination of U0126 and T0901317 maintained arterial wall integrity, inhibited macrophage accumulation in aortas and formation of macrophages/foam cells, and activated reverse cholesterol transport. The inhibition of T0901317-induced lipid accumulation by the combined U0126 might be attributed to inactivation of lipogenesis and activation of lipolysis/fatty acid oxidation pathways. CONCLUSIONS: Our study suggests that the combination of mitogen-activated protein kinase kinase 1/2 inhibitor and LXR ligand can function as a novel therapy to synergistically reduce atherosclerosis while eliminating LXR-induced deleterious effects.
OBJECTIVE: Activation of liver X receptor (LXR) inhibits atherosclerosis but induces hypertriglyceridemia. In vitro, it has been shown that mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor synergizes LXR ligand-induced macrophage ABCA1 expression and cholesterol efflux. In this study, we determined whether MEK1/2 (U0126) and LXR ligand (T0901317) can have a synergistic effect on the reduction of atherosclerosis while eliminating LXR ligand-induced fatty livers and hypertriglyceridemia. We also set out to identify the cellular mechanisms of the actions. APPROACH AND RESULTS: Wild-type mice were used to determine the effect of U0126 on a high-fat diet or high-fat diet plus T0901317-induced transient dyslipidemia and liver injury. ApoE deficient (apoE(-/-)) mice or mice with advanced lesions were used to determine the effect of the combination of T0901317 and U0126 on atherosclerosis and hypertriglyceridemia. We found that U0126 protected animals against T0901317-induced transient or long-term hepatic lipid accumulation, liver injury, and hypertriglyceridemia. Meanwhile, the combination of T0901317 and U0126 inhibited the development of atherosclerosis in a synergistic manner and reduced advanced lesions. Mechanistically, in addition to synergistic induction of macrophage ABCA1 expression, the combination of U0126 and T0901317 maintained arterial wall integrity, inhibited macrophage accumulation in aortas and formation of macrophages/foam cells, and activated reverse cholesterol transport. The inhibition of T0901317-induced lipid accumulation by the combined U0126 might be attributed to inactivation of lipogenesis and activation of lipolysis/fatty acid oxidation pathways. CONCLUSIONS: Our study suggests that the combination of mitogen-activated protein kinase kinase 1/2 inhibitor and LXR ligand can function as a novel therapy to synergistically reduce atherosclerosis while eliminating LXR-induced deleterious effects.
Authors: Matthew E Long; William E Eddy; Ke-Qin Gong; Lara L Lovelace-Macon; Ryan S McMahan; Jean Charron; W Conrad Liles; Anne M Manicone Journal: J Immunol Date: 2016-12-21 Impact factor: 5.422
Authors: Matthew E Long; Ke-Qin Gong; William E Eddy; Joseph S Volk; Eric D Morrell; Carmen Mikacenic; T Eoin West; Shawn J Skerrett; Jean Charron; W Conrad Liles; Anne M Manicone Journal: JCI Insight Date: 2019-12-05