Alterations of plasma lipids in mice via adenoviral-mediated hepatic overexpression of human ABCA1.
ATP binding cassette transporter A1 (ABCA1) is a widely expressed lipid transporter essential for the generation of HDL. ABCA1 is particularly abundant in the liver, suggesting that the liver may play a major role in HDL homeostasis. To determine how hepatic ABCA1 affects plasma HDL cholesterol levels, we treated mice with an adenovirus (Ad)-expressing human ABCA1 under the control of the cytomegalovirus promoter. Treated mice showed a dose-dependent increase in hepatic ABCA1 protein, ranging from 1.2-fold to 8.3-fold using doses from 5 x 108 to 1.5 x 109 pfu, with maximal expression observed on Day 3 posttreatment. A selective increase in HDL cholesterol occurred at Day 3 in mice treated with 5 x 108 pfu Ad-ABCA1, but higher doses did not further elevate HDL cholesterol levels. In contrast, total cholesterol, triglycerides, phospholipids, non-HDL cholesterol, and apolipoprotein B levels all increased in a dose-dependent manner, suggesting that excessive overexpression of hepatic ABCA1 in the absence of its normal regulatory sequences altered total lipid homeostasis. At comparable expression levels, bacterial artificial chromosome transgenic mice, which express ABCA1 under the control of its endogenous regulatory sequences, showed a greater and more specific increase in HDL cholesterol than Ad-ABCA1-treated mice. Our results suggest that appropriate regulation of ABCA1 is critical for a selective increase in HDL cholesterol levels.
Centre for Molecular Medicine and Therapeutics, British Columbia Children's and Women's Hospital, University of British Columbia, Vancouver, BC, Canada.
Cheryl L
CL
Wellington
Liam R
LR
Brunham
Steven
S
Zhou
Roshni R
RR
Singaraja
Henk
H
Visscher
Allison
A
Gelfer
Colin
C
Ross
Erick
E
James
Guoqing
G
Liu
Mary T
MT
Huber
Yu-Zhou
YZ
Yang
Robin J
RJ
Parks
Albert
A
Groen
Jamila
J
Fruchart-Najib
Michael R
MR
Hayden
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D008076:Cholesterol, HDL / Q000097:blood; D015870:Gene Expression; D005822:Genetic Vectors; D006801:Humans; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010743:Phospholipids / Q000097:blood; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D008055:Lipids; D010743:Phospholipids; D011994:Recombinant Proteins