title: ORP4L Facilitates Macrophage Survival via G-Protein-Coupled Signaling: ORP4L-/- Mice Display a Reduction of Atherosclerosis.
abstract: BACKGROUND
  Macrophage survival within the arterial wall is a central factor contributing to atherogenesis. Oxysterols, major components of oxidized low-density lipoprotein, exert cytotoxic effects on macrophages.
  
  
  OBJECTIVE
  To determine whether oxysterol-binding protein-related protein 4 L (ORP4L), an oxysterol-binding protein, affects macrophage survival and the pathogenesis of atherosclerosis.
  
  
  RESULTS
  By hiring cell biological approaches and ORP4L-/-mice, we show that ORP4L coexpresses with and forms a complex with Gαq/11and phospholipase C (PLC)-β3 in macrophages. ORP4L facilitates G-protein-coupled ligand-induced PLCβ3 activation, IP3production, and Ca2+release from the endoplasmic reticulum. Through this mechanism, ORP4L sustains antiapoptotic Bcl-XL expression through Ca2+-mediated c-AMP responsive element binding protein transcriptional regulation and thus protects macrophages from apoptosis. Excessive stimulation with the oxysterol 25-hydroxycholesterol disassembles the ORP4L/Gαq/11/PLCβ3 complexes, resulting in reduced PLCβ3 activity, IP3production, and Ca2+release, as well as decreased Bcl-XL expression and increased apoptosis. Overexpression of ORP4L counteracts these oxysterol-induced defects. Mice lacking ORP4L exhibit increased apoptosis of macrophages in atherosclerotic lesions and a reduced lesion size.
  
  
  CONCLUSIONS
  ORP4L is crucial for macrophage survival. It counteracts the cytotoxicity of oxysterols/oxidized low-density lipoprotein to protect macrophage from apoptosis, thus playing an important role in the development of atherosclerosis.
authors.affiliation: From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China (W.Z., G.P., L.W., J.L., B.Z., X.C., H.M., C.L., D.Y.); Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland (S.L., V.M.O.); Division of Cardiac Surgery, the First Affiliated Hospital (J.O.) and Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (M.X., J.X.); and U1011 Inserm, EGID, Université Lille, CHU Lille, Institut Pasteur de Lille, France (B.S.).
authors.forename: Wenbin
authors.initials: W
authors.lastname: Zhong
authors.affiliation: From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China (W.Z., G.P., L.W., J.L., B.Z., X.C., H.M., C.L., D.Y.); Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland (S.L., V.M.O.); Division of Cardiac Surgery, the First Affiliated Hospital (J.O.) and Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (M.X., J.X.); and U1011 Inserm, EGID, Université Lille, CHU Lille, Institut Pasteur de Lille, France (B.S.).
authors.forename: Guoping
authors.initials: G
authors.lastname: Pan
authors.affiliation: From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Department of Biotechnology, College of Life Science and Technology, Jinan University, Guangzhou, China (W.Z., G.P., L.W., J.L., B.Z., X.C., H.M., C.L., D.Y.); Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland (S.L., V.M.O.); Division of Cardiac Surgery, the First Affiliated Hospital (J.O.) and Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China (M.X., J.X.); and U1011 Inserm, EGID, Université Lille, CHU Lille, Institut Pasteur de Lille, France (B.S.).
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Shiqian
authors.initials: S
authors.lastname: Li
authors.forename: Jingsong
authors.initials: J
authors.lastname: Ou
authors.forename: Mengyang
authors.initials: M
authors.lastname: Xu
authors.forename: Jiwei
authors.initials: J
authors.lastname: Li
authors.forename: Biying
authors.initials: B
authors.lastname: Zhu
authors.forename: Xiuye
authors.initials: X
authors.lastname: Cao
authors.forename: Hongling
authors.initials: H
authors.lastname: Ma
authors.forename: Chaowen
authors.initials: C
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Vesa M
authors.initials: VM
authors.lastname: Olkkonen
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Daoguang
authors.initials: D
authors.lastname: Yan
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000098825:Oxysterol Binding Proteins
chemical_list: D043562:Receptors, G-Protein-Coupled; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins
keywords: apoptosis; atherosclerosis; bcl-XL protein; macrophages; oxidized low density lipoprotein