title: ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol efflux to plasma.
abstract: ApoE plays an important role in lipoprotein metabolism. This study investigated the effects of adenovirus-mediated human apoE overexpression (AdhApoE3) on sterol metabolism and in vivo reverse cholesterol transport (RCT). In wild-type mice, AdhApoE3 resulted in decreased HDL cholesterol levels and a shift toward larger HDL in plasma, whereas hepatic cholesterol content increased (P < 0.05). These effects were dependent on scavenger receptor class B type I (SR-BI) as confirmed using SR-BI-deficient mice. Kinetic studies demonstrated increased plasma HDL cholesteryl ester catabolic rates (P < 0.05) and higher hepatic selective uptake of HDL cholesteryl esters in AdhApoE3-injected wild-type mice (P < 0.01). However, biliary and fecal sterol output as well as in vivo macrophage-to-feces RCT studied with (3)H-cholesterol-loaded mouse macrophage foam cells remained unchanged upon human apoE overexpression. Similar results were obtained using hApoE3 overexpression in human CETP transgenic mice. However, blocking ABCA1-mediated cholesterol efflux from hepatocytes in AdhApoE3-injected mice using probucol increased biliary cholesterol secretion (P < 0.05), fecal neutral sterol excretion (P < 0.05), and in vivo RCT (P < 0.01), specifically within neutral sterols. These combined data demonstrate that systemic apoE overexpression increases i) SR-BI-mediated selective uptake into the liver and ii) ABCA1-mediated efflux of RCT-relevant cholesterol from hepatocytes back to the plasma compartment, thereby resulting in unchanged fecal mass sterol excretion and overall in vivo RCT.
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands.
authors.forename: Wijtske
authors.initials: W
authors.lastname: Annema
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Arne
authors.initials: A
authors.lastname: Dikkers
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Freark de Boer
authors.affiliation: INSERM UMR866 Lipides, Nutrition, Cancer, Faculté de Médecine, Dijon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gautier
authors.affiliation: Department of General Internal Medicine, Endocrinology, and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands; and.
authors.forename: Patrick C N
authors.initials: PCN
authors.lastname: Rensen
authors.affiliation: Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Top Institute Food and Nutrition, Wageningen, The Netherlands. Electronic address: u_tietge@yahoo.com.
authors.forename: Uwe J F
authors.initials: UJF
authors.lastname: Tietge
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism*; D001659:Biliary Tract / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D018955:CD36 Antigens / Q000378:metabolism; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000737:chemistry / Q000378:metabolism*; D005243:Feces; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010316:Particle Size; D011341:Probucol / Q000494:pharmacology
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D053318:Apolipoprotein E3; D018955:CD36 Antigens; D008076:Cholesterol, HDL; D002784:Cholesterol; D011341:Probucol