title: Enhanced HDL Functionality in Small HDL Species Produced Upon Remodeling of HDL by Reconstituted HDL, CSL112: Effects on Cholesterol Efflux, Anti-Inflammatory and Antioxidative Activity.
abstract: BACKGROUND
  CSL112, human apolipoprotein A-I (apoA-I) reconstituted with phosphatidylcholine, is known to cause a dramatic rise in small high-density lipoprotein (HDL).
  
  
  OBJECTIVE
  To explore the mechanisms by which the formation of small HDL particles is induced by CSL112.
  
  
  RESULTS
  Infusion of CSL112 into humans caused elevation of 2 small diameter HDL fractions and 1 large diameter fraction. Ex vivo studies showed that this remodeling does not depend on lipid transfer proteins or lipases. Rather, interaction of CSL112 with purified HDL spontaneously gave rise to 3 HDL species: a large, spherical species composed of apoA-I from native HDL and CSL112; a small, disc-shaped species composed of apoA-I from CSL112, but smaller because of the loss of phospholipids; and the smallest species, lipid-poor apoA-I composed of apoA-I from HDL and CSL112. Time-course studies suggest that remodeling occurs by an initial fusion of CSL112 with HDL and subsequent fission leading to the smaller forms. Functional studies showed that ATP-binding cassette transporter 1-dependent cholesterol efflux and anti-inflammatory effects in whole blood were carried by the 2 small species with little activity in the large species. In contrast, the ability to inactivate lipid hydroperoxides in oxidized low-density lipoprotein was carried predominantly by the 2 largest species and was low in lipid-poor apoA-I.
  
  
  CONCLUSIONS
  We have described a mechanism for the formation of small, highly functional HDL species involving spontaneous fusion of discoidal HDL with spherical HDL and subsequent fission. Similar remodeling is likely to occur during the life cycle of apoA-I in vivo.
authors.affiliation: From the CSL Behring AG, Berne, Switzerland (S.A.D., A.V.N., P.S., M.O.S.); National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, Paris, France (A.M.O.C., M.J.C., A.K.); University of Pierre and Marie Curie - Paris 6, France (A.M.O.C., M.J.C., A.K.); Pitié - Salpétrière University Hospital; ICAN, Paris, France (A.M.O.C., M.J.C., A.K.); CSL Limited, Parkville, VIC, Australia (A.G.); AP-HP, HUPS Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (P.T.); and CSL Behring, King of Prussia, PA (S.D.W.).
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Didichenko
authors.affiliation: From the CSL Behring AG, Berne, Switzerland (S.A.D., A.V.N., P.S., M.O.S.); National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, Paris, France (A.M.O.C., M.J.C., A.K.); University of Pierre and Marie Curie - Paris 6, France (A.M.O.C., M.J.C., A.K.); Pitié - Salpétrière University Hospital; ICAN, Paris, France (A.M.O.C., M.J.C., A.K.); CSL Limited, Parkville, VIC, Australia (A.G.); AP-HP, HUPS Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (P.T.); and CSL Behring, King of Prussia, PA (S.D.W.).
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Navdaev
authors.affiliation: From the CSL Behring AG, Berne, Switzerland (S.A.D., A.V.N., P.S., M.O.S.); National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, Paris, France (A.M.O.C., M.J.C., A.K.); University of Pierre and Marie Curie - Paris 6, France (A.M.O.C., M.J.C., A.K.); Pitié - Salpétrière University Hospital; ICAN, Paris, France (A.M.O.C., M.J.C., A.K.); CSL Limited, Parkville, VIC, Australia (A.G.); AP-HP, HUPS Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (P.T.); and CSL Behring, King of Prussia, PA (S.D.W.).
authors.forename: Alexandre M O
authors.initials: AM
authors.lastname: Cukier
authors.affiliation: From the CSL Behring AG, Berne, Switzerland (S.A.D., A.V.N., P.S., M.O.S.); National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, Paris, France (A.M.O.C., M.J.C., A.K.); University of Pierre and Marie Curie - Paris 6, France (A.M.O.C., M.J.C., A.K.); Pitié - Salpétrière University Hospital; ICAN, Paris, France (A.M.O.C., M.J.C., A.K.); CSL Limited, Parkville, VIC, Australia (A.G.); AP-HP, HUPS Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (P.T.); and CSL Behring, King of Prussia, PA (S.D.W.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Gille
authors.affiliation: From the CSL Behring AG, Berne, Switzerland (S.A.D., A.V.N., P.S., M.O.S.); National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, Paris, France (A.M.O.C., M.J.C., A.K.); University of Pierre and Marie Curie - Paris 6, France (A.M.O.C., M.J.C., A.K.); Pitié - Salpétrière University Hospital; ICAN, Paris, France (A.M.O.C., M.J.C., A.K.); CSL Limited, Parkville, VIC, Australia (A.G.); AP-HP, HUPS Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (P.T.); and CSL Behring, King of Prussia, PA (S.D.W.).
authors.forename: Patrick
authors.initials: P
authors.lastname: Schuetz
authors.affiliation: From the CSL Behring AG, Berne, Switzerland (S.A.D., A.V.N., P.S., M.O.S.); National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, Paris, France (A.M.O.C., M.J.C., A.K.); University of Pierre and Marie Curie - Paris 6, France (A.M.O.C., M.J.C., A.K.); Pitié - Salpétrière University Hospital; ICAN, Paris, France (A.M.O.C., M.J.C., A.K.); CSL Limited, Parkville, VIC, Australia (A.G.); AP-HP, HUPS Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (P.T.); and CSL Behring, King of Prussia, PA (S.D.W.).
authors.forename: Martin O
authors.initials: MO
authors.lastname: Spycher
authors.affiliation: From the CSL Behring AG, Berne, Switzerland (S.A.D., A.V.N., P.S., M.O.S.); National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, Paris, France (A.M.O.C., M.J.C., A.K.); University of Pierre and Marie Curie - Paris 6, France (A.M.O.C., M.J.C., A.K.); Pitié - Salpétrière University Hospital; ICAN, Paris, France (A.M.O.C., M.J.C., A.K.); CSL Limited, Parkville, VIC, Australia (A.G.); AP-HP, HUPS Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (P.T.); and CSL Behring, King of Prussia, PA (S.D.W.).
authors.forename: Patrice
authors.initials: P
authors.lastname: Thérond
authors.affiliation: From the CSL Behring AG, Berne, Switzerland (S.A.D., A.V.N., P.S., M.O.S.); National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, Paris, France (A.M.O.C., M.J.C., A.K.); University of Pierre and Marie Curie - Paris 6, France (A.M.O.C., M.J.C., A.K.); Pitié - Salpétrière University Hospital; ICAN, Paris, France (A.M.O.C., M.J.C., A.K.); CSL Limited, Parkville, VIC, Australia (A.G.); AP-HP, HUPS Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (P.T.); and CSL Behring, King of Prussia, PA (S.D.W.).
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.affiliation: From the CSL Behring AG, Berne, Switzerland (S.A.D., A.V.N., P.S., M.O.S.); National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, Paris, France (A.M.O.C., M.J.C., A.K.); University of Pierre and Marie Curie - Paris 6, France (A.M.O.C., M.J.C., A.K.); Pitié - Salpétrière University Hospital; ICAN, Paris, France (A.M.O.C., M.J.C., A.K.); CSL Limited, Parkville, VIC, Australia (A.G.); AP-HP, HUPS Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (P.T.); and CSL Behring, King of Prussia, PA (S.D.W.).
authors.forename: Anatol
authors.initials: A
authors.lastname: Kontush
authors.affiliation: From the CSL Behring AG, Berne, Switzerland (S.A.D., A.V.N., P.S., M.O.S.); National Institute for Health and Medical Research (INSERM), UMR-ICAN 1166, Paris, France (A.M.O.C., M.J.C., A.K.); University of Pierre and Marie Curie - Paris 6, France (A.M.O.C., M.J.C., A.K.); Pitié - Salpétrière University Hospital; ICAN, Paris, France (A.M.O.C., M.J.C., A.K.); CSL Limited, Parkville, VIC, Australia (A.G.); AP-HP, HUPS Hôpital de Bicêtre, Le Kremlin-Bicêtre, France (P.T.); and CSL Behring, King of Prussia, PA (S.D.W.). samuel.wright@cslbehring.com.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000378:metabolism*; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism*; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D007262:Infusions, Intravenous; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; C584257:CSL112; D008075:Lipoproteins, HDL; D002784:Cholesterol
keywords: antioxidant; apolipoprotein A-I; cholesterol; high-density lipoproteins; inflammation