title: Hepatic ATP-binding cassette transporter A1 is a key molecule in high-density lipoprotein cholesteryl ester metabolism in mice.
abstract: OBJECTIVE
  Mutations in ATP-binding cassette transporter A1 (ABCA1), the cellular lipid transport molecule mutated in Tangier disease, result in the rapid turnover of high-density lipoprotein (HDL)-associated apolipoproteins that presumably are cleared by the kidneys. However, the role of ABCA1 in the liver for HDL apolipoprotein and cholesteryl ester (CE) catabolism in vivo is unknown.
  
  
  RESULTS
  Murine HDL was radiolabeled with 125I in its apolipoprotein and with [3H]cholesteryl oleyl ether in its CE moiety. HDL protein and lipid metabolism in plasma and HDL uptake by tissues were investigated in ABCA1-overexpressing bacterial artificial chromosome (BAC)-transgenic (BAC+) mice and in mice harboring deletions of total (ABCA1-/-) and liver-specific ABCA1 (ABCA1(-L/-L)). In BAC+ mice with elevated ABCA1 expression, fractional catabolic rates (FCRs) of both the protein and the lipid tracer were significantly decreased in plasma and in the liver, yielding a diminished hepatic selective CE uptake from HDL. In contrast, ABCA1-/- or ABCA1(-L/-L) mice had significantly increased plasma and liver FCRs for both HDL tracers. An ABCA1 deficiency was associated with increased selective HDL CE uptake by the liver under all experimental conditions.
  
  
  CONCLUSIONS
  Hepatic ABCA1 has a critical role for HDL catabolism in plasma and for HDL selective CE uptake by the liver.
authors.affiliation: University of British Columbia, Vancouver, Canada.
authors.forename: Roshni R
authors.initials: RR
authors.lastname: Singaraja
authors.forename: Bjorn
authors.initials: B
authors.lastname: Stahmer
authors.forename: May
authors.initials: M
authors.lastname: Brundert
authors.forename: Martin
authors.initials: M
authors.lastname: Merkel
authors.forename: Joerg
authors.initials: J
authors.lastname: Heeren
authors.forename: Nagat
authors.initials: N
authors.lastname: Bissada
authors.forename: Martin
authors.initials: M
authors.lastname: Kang
authors.forename: Jenelle M
authors.initials: JM
authors.lastname: Timmins
authors.forename: Rajasekhar
authors.initials: R
authors.lastname: Ramakrishnan
authors.forename: John S
authors.initials: JS
authors.lastname: Parks
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Franz
authors.initials: F
authors.lastname: Rinninger
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000097:blood; D002788:Cholesterol Esters / Q000378:metabolism*; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008822:Mice, Transgenic / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002788:Cholesterol Esters; D008075:Lipoproteins, HDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D002784:Cholesterol