title: Reconstituted high-density lipoprotein can elevate plasma alanine aminotransferase by transient depletion of hepatic cholesterol: role of the phospholipid component.
abstract: Human apolipoprotein A-I preparations reconstituted with phospholipids (reconstituted high-density lipoprotein [HDL]) have been used in a large number of animal and human studies to investigate the physiological role of apolipoprotein A-I. Several of these studies observed that intravenous infusion of reconstituted HDL might cause transient elevations in plasma levels of hepatic enzymes. Here we describe the mechanism of this enzyme release. Observations from several animal models and in vitro studies suggest that the extent of hepatic transaminase release (alanine aminotransferase [ALT]) correlates with the movement of hepatic cholesterol into the blood after infusion. Both the amount of ALT release and cholesterol movement were dependent on the amount and type of phospholipid present in the reconstituted HDL. As cholesterol is known to dissolve readily in phospholipid, an HDL preparation was loaded with cholesterol before infusion into rats to assess the role of diffusion of cholesterol out of the liver and into the reconstituted HDL. Cholesterol-loaded HDL failed to withdraw cholesterol from tissues and subsequently failed to cause ALT release. To investigate further the role of cholesterol diffusion, we employed mice deficient in SR-BI, a transporter that facilitates spontaneous movement of cholesterol between cell membranes and HDL. These mice showed substantially lower movement of cholesterol into the blood and markedly lower ALT release. We conclude that initial depletion of hepatic cholesterol initiates transient ALT release in response to infusion of reconstituted HDL. This effect may be controlled by appropriate choice of the type and amount of phospholipid in reconstituted HDL. Copyright © 2015 John Wiley & Sons, Ltd.
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, 35041, Marburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Herzog
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, 35041, Marburg, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Pragst
authors.affiliation: CSL Behring AG, Quality Management, 3000, Bern, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Waelchli
authors.affiliation: CSL Ltd, Clinical and Translational Sciences, Melbourne, Victoria, 3052, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Gille
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, 35041, Marburg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schenk
authors.affiliation: CSL Behring GmbH, Preclinical Research and Development, 35041, Marburg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Mueller-Cohrs
authors.affiliation: CSL Behring AG, Research and Development, 3000, Bern, Switzerland.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Diditchenko
authors.affiliation: Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Paolo
authors.initials: P
authors.lastname: Zanoni
authors.affiliation: Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Cuchel
authors.affiliation: Philipps Universitaet, Faculty of Chemistry, 35032, Marburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Seubert
authors.affiliation: Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: CSL Behring, Research, King of Prussia, PA, 19406, USA.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D061605:Administration, Intravenous; D000410:Alanine Transaminase / Q000097:blood*; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D008401:Gas Chromatography-Mass Spectrometry; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010743:Phospholipids / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D018955:CD36 Antigens; D008076:Cholesterol, HDL; D010743:Phospholipids; C001521:lathosterol; D002784:Cholesterol; D000410:Alanine Transaminase
keywords: hepatic; lipids; liver; mechanisms; toxicity