In vivo modulation of HDL phospholipid has opposing effects on SR-BI- and ABCA1-mediated cholesterol efflux.
The effects of in vivo modulation of HDL phospholipid (PL) on scavenger receptor class BI (SR-BI)- and ATP binding cassette transporter 1 (ABCA1)-mediated efflux were examined by overexpressing either endothelial lipase (EL) or phosphatidylserine phospholipase (PS-PLA1) in human apolipoprotein A-I (apoA-I) transgenic mice. Overexpression of EL led to large reductions in the serum PL/apoA-I ratio (-60%), total cholesterol (TC; -89%), and HDL cholesterol (-91%). Relative to the serum before overexpression of EL, the efflux potential of the serum via SR-BI decreased by 90% and ABCA1-mediated efflux increased by 63%. In contrast to overexpression of EL, overexpression of PS-PLA1 led to increases in the PL/apoA-I ratio (88%), TC (78%), HDL cholesterol (57%), and HDL size. The efflux potential of the serum increased by 60% via SR-BI and decreased by 57% via ABCA1. There were significant positive correlations between SR-BI-mediated efflux and a number of serum parameters, including PL/apoA-I ratio, PL, TC, free cholesterol (FC), and HDL cholesterol. In striking contrast, the same correlations were seen with ABCA1-mediated efflux, but the relationships were inverse. In summary, in vivo modulation of HDL PL content affects ABCA1- and SR-BI-mediated efflux in a reciprocal manner. These findings indicate that the type of lipase acting on HDL in vivo will determine which FC efflux pathway the HDL serves. Additionally, the extent of lipolysis will determine the efficiency of FC removal via this pathway.
Division of Gastroenterology and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Patricia G
PG
Yancey
Masa-aki
MA
Kawashiri
Ryan
R
Moore
Jane M
JM
Glick
David L
DL
Williams
Margery A
MA
Connelly
Daniel J
DJ
Rader
George H
GH
Rothblat
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000256:Adenoviridae; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D018955:CD36 Antigens; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D005260:Female; D006801:Humans; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis / Q000502:physiology; D008075:Lipoproteins, HDL / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010740:Phospholipases / Q000235:genetics / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D051116:Receptors, Scavenger; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D018955:CD36 Antigens; D008075:Lipoproteins, HDL; D010743:Phospholipids; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D011994:Recombinant Proteins; D002784:Cholesterol; D010740:Phospholipases; D008049:Lipase