Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL cholesterol concentrations.
The current model for reverse cholesterol transport proposes that HDL transports excess cholesterol derived primarily from peripheral cells to the liver for removal. However, recent studies in ABCA1 transgenic mice suggest that the liver itself may be a major source of HDL cholesterol (HDL-C). To directly investigate the hepatic contribution to plasma HDL-C levels, we generated an adenovirus (rABCA1-GFP-AdV) that targets expression of mouse ABCA1-GFP in vivo to the liver. Compared with mice injected with control AdV, infusion of rABCA1-GFP-AdV into C57Bl/6 mice resulted in increased expression of mouse ABCA1 mRNA and protein in the liver. ApoA-I-dependent cholesterol efflux was increased 2.6-fold in primary hepatocytes isolated 1 day after rABCA1-GFP-AdV infusion. Hepatic ABCA1 expression in C57Bl/6 mice (n = 15) raised baseline levels of TC, PL, FC, HDL-C, apoE, and apoA-I by 150-300% (P < 0.05 all). ABCA1 expression led to significant compensatory changes in expression of genes that increase hepatic cholesterol, including HMG-CoA reductase (3.5-fold), LDLr (2.1-fold), and LRP (5-fold) in the liver. These combined results demonstrate that ABCA1 plays a key role in hepatic cholesterol efflux, inducing pathways that modulate cholesterol homeostasis in the liver, and establish the liver as a major source of plasma HDL-C.
Basso
Federica
F
Molecular Disease Branch, NHLBI, National Institutes of Health, Bethesda, MD 20862, USA. fbasso@mail.nih.gov
Freeman
Lita
L
Knapper
Catherine L
CL
Remaley
Alan
A
Stonik
John
J
Neufeld
Edward B
EB
Tansey
Terese
T
Amar
Marcelo J A
MJ
Fruchart-Najib
Jamila
J
Duverger
Nicholas
N
Santamarina-Fojo
Silvia
S
Brewer
H Bryan
HB
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D008055:Lipids; D008074:Lipoproteins; D011993:Recombinant Fusion Proteins; D002784:Cholesterol