title: Hypocholesterolemia, foam cell accumulation, but no atherosclerosis in mice lacking ABC-transporter A1 and scavenger receptor BI.
abstract: High-density lipoprotein (HDL) mediated reverse cholesterol transport (RCT) is regarded to be crucial for prevention of foam cell formation and atherosclerosis. ABC-transporter A1 (ABCA1) and scavenger receptor BI (SR-BI) are involved in the biogenesis of HDL and the selective delivery of HDL cholesterol to the liver, respectively. In the present study, we phenotypically characterized mice lacking these two proteins essential for HDL metabolism. ABCA1×SR-BI double knockout (dKO) mice showed severe hypocholesterolemia mainly due to HDL loss, despite a 90% reduction of HDL cholesterol uptake by liver. VLDL production was increased in dKO mice. However, non-HDL cholesterol levels were reduced, probably due to enhanced clearance via LRP1. Hepatobiliary cholesterol transport and fecal sterol excretion were not impaired in dKO mice. In contrast, the macrophage RCT in dKO mice was markedly impaired as compared to WT mice, associated with the accumulation of macrophage foam cells in the lung and Peyer's patches. Strikingly, no atherosclerotic lesion formation was observed in dKO mice. In conclusion, both ABCA1 and SR-BI are essential for maintaining a properly functioning HDL-mediated macrophage RCT, while the potential anti-atherosclerotic functions of ABCA1 and SR-BI are not evident in dKO mice due to the absence of pro-atherogenic lipoproteins.
authors.affiliation: Division of Biopharmaceutics, Leiden University, Leiden, The Netherlands. y.zhao@lacdr.leidenuniv.nl
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhao
authors.forename: Marieke
authors.initials: M
authors.lastname: Pennings
authors.forename: Carlos L J
authors.initials: CL
authors.lastname: Vrins
authors.forename: Laura
authors.initials: L
authors.lastname: Calpe-Berdiel
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
authors.forename: J Kar
authors.initials: JK
authors.lastname: Kruijt
authors.forename: Roelof
authors.initials: R
authors.lastname: Ottenhoff
authors.forename: Reeni B
authors.initials: RB
authors.lastname: Hildebrand
authors.forename: Ronald
authors.initials: R
authors.lastname: van der Sluis
authors.forename: Wendy
authors.initials: W
authors.lastname: Jessup
authors.forename: Wilfried
authors.initials: W
authors.lastname: Le Goff
authors.forename: M John
authors.initials: MJ
authors.lastname: Chapman
authors.forename: Thierry
authors.initials: T
authors.lastname: Huby
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D050171:Dyslipidemias / Q000378:metabolism*; D005260:Female; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism*; D050356:Lipid Metabolism; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013997:Time Factors
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D002784:Cholesterol