title: Abnormal phospholipid composition impairs HDL biogenesis and maturation in mice lacking Abca1.
abstract: Recent studies have demonstrated that the ATP-binding cassette transporter A1 (ABCA1) facilitates the efflux of phospholipids and cholesterol to apoprotein acceptors, leading to the synthesis of HDL. The purpose of this study was to determine the changes in the lipoprotein fractions in Abca1-deficient mice and study the mechanisms responsible for the low levels of HDL when ABCA1 is absent. Plasma phospholipid concentration was decreased by more than 75%, mostly due to a reduction of phosphatidylcholine (PC) in HDL. Abca1(-/-) HDL represents less than 2% of wild-type levels and is smaller and enriched in phospholipids (11.2-fold more than HDL from controls). Compared to wild-type littermates, Abca1(-/-) HDL had a 4-fold increase in PC, whereas lysophosphatidylcholine (LPC) (125-fold), sphingomyelin (SPH) (49-fold), and phosphatidylethanolamine (PE) (18-fold) showed even higher increases. As a consequence, the ratios of LPC/PC, SPH/PC, PE/PC, and phosphatidylinositol + phosphatidylserine (PI+PS)/PC were all much higher in HDL from Abca1(-/-), compared to wild-type HDL. Plasma phospholipid transfer protein (PLTP) and lecithin cholesterol acyltransferase (LCAT) activities were decreased by more than 80%, suggesting that the maturation of HDL is affected. To test this hypothesis, plasma from Abca1(-/-) mice was incubated with CHO cells that are known to express high levels of ABCA1 with the intent of restoring the flux of phospholipid and cholesterol onto apoAI. Compared to native plasma, no change in maturation of HDL was observed. In contrast, a 220% increase in the formation of mature HDL was observed when ABCA1 function and LCAT activities were restored. Taken together, these observations suggest that ABCA1 is necessary for the adequate lipidation of apoAI, which enables the interaction with LCAT and subsequent maturation.
authors.affiliation: Pfizer Global Research and Development, Groton, Connecticut 06340, USA. Omar_L_Francone@groton.pfizer.com
authors.forename: Omar L
authors.initials: OL
authors.lastname: Francone
authors.forename: Papasani V
authors.initials: PV
authors.lastname: Subbaiah
authors.forename: Arie
authors.initials: A
authors.lastname: van Tol
authors.forename: Lori
authors.initials: L
authors.lastname: Royer
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Haghpassand
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D007413:Intestinal Mucosa / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010743:Phospholipids / Q000097:blood*; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D010743:Phospholipids; D012333:RNA, Messenger; D002784:Cholesterol