on July 3, 2008
Published online before print July 3, 2008, doi: 10.1161/ATVBAHA.108.168542
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Submitted on January 3, 2008
Accepted on June 23, 2008
Overexpression of Human ABCG1 Does Not Affect Atherosclerosis in Fat-Fed ApoE-Deficient Mice
Braydon Burgess ;
From the Department of Pathology and Laboratory Medicine (B.B., K.N., J.C., V.H.-R., G.T., A.W., J.F., J.D., D.B., T.T., G.O., C.W.), Child and Family Research Institute, University of British Columbia, Vancouver, Canada; ICapture Centre (L.M., B.M.), University of British Columbia, Vancouver, Canada; the Department of Pediatrics (B.C., R.D., S.I.), Child and Family Research Institute, University of British Columbia, Vancouver, Canada; and the Department of Clinical Pharmacology (D.L.), University of Bonn, Germany.
* To whom correspondence should be addressed. E-mail: Cheryl{at}cmmt.ubc.ca.
Objective—The purpose of this study was to evaluate the effects of whole body overexpression of human ABCG1 on atherosclerosis in apoE-/- mice.
Methods and Results—We generated BAC transgenic mice in which human ABCG1 is expressed from endogenous regulatory signals, leading to a 3- to 7-fold increase in ABCG1 protein across various tissues. Although the ABCG1 BAC transgene rescued lung lipid accumulation in ABCG1-/- mice, it did not affect plasma lipid levels, macrophage cholesterol efflux to HDL, atherosclerotic lesion area in apoE-/- mice, or levels of tissue cholesterol, cholesterol ester, phospholipids, or triglycerides. Subtle changes in sterol biosynthetic intermediate levels were observed in liver, with chow-fed ABCG1 BAC Tg mice showing a nonsignificant trend toward decreased levels of lathosterol, lanosterol, and desmosterol, and fat-fed mice exhibiting significantly elevated levels of each intermediate. These changes were insufficient to alter ABCA1 expression in liver.
Conclusions—Transgenic human ABCG1 does not influence atherosclerosis in apoE-/- mice but may participate in the regulation of tissue cholesterol biosynthesis.
Key words: ABCG1 • cholesterol • atherosclerosis • cholesterol intermediate