title: Inhibition of ERK1/2 and activation of LXR synergistically reduce atherosclerotic lesions in ApoE-deficient mice.
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.
  
  
  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: 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.).
authors: Yuanli
authors: Y
authors: Chen
authors: 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.).
authors: Yajun
authors: Y
authors: Duan
authors: 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.).
authors: Xiaoxiao
authors: X
authors: Yang
authors: 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.).
authors: Lei
authors: L
authors: Sun
authors: 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.).
authors: Mengyang
authors: M
authors: Liu
authors: 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.).
authors: Qixue
authors: Q
authors: Wang
authors: 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.).
authors: Xingzhe
authors: X
authors: Ma
authors: 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.).
authors: Wenwen
authors: W
authors: Zhang
authors: 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.).
authors: Xiaoju
authors: X
authors: Li
authors: 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.).
authors: Wenquan
authors: W
authors: Hu
authors: 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.).
authors: Robert Q
authors: RQ
authors: Miao
authors: 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.).
authors: Rong
authors: R
authors: Xiang
authors: 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.).
authors: David P
authors: DP
authors: Hajjar
authors: 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.
authors: Jihong
authors: J
authors: Han
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D002070:Butadienes / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005234:Fatty Liver / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D005260:Female; D005487:Foam Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology* / Q000633:toxicity; D015228:Hypertriglyceridemia / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000633:toxicity; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D001057:Apolipoproteins E; D002070:Butadienes; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009570:Nitriles; D057093:Orphan Nuclear Receptors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C113580:U 0126; C535148:Mapk1 protein, mouse
keywords: atherosclerosis; extracellular signal-regulated map kinases; foam cells; hypertriglyceridemia; lipogenesis; liver X receptor