ABCA1: Role in Atherosclerosis: The identification of ATP binding cassette transporter AI (ABCA1) as the lipid transporter defective in Tangier disease has generated interest in modulating human plasma HDL levels and atherogenic risk by enhancing ABCA1 gene expression. To investigate the role that increased ABCA1 gene expression plays in the development of atherosclerosis we placed mice overexpressing hABCA1 (hABCA1-Tg) on an atherogenic diet. ABCA1 altered the lipoprotein response to dietary cholesterol in C57Bl/6 mice leading to decreased plasma cholesterol, CE, FC, nonHDL-C and apoA-I levels and increased plasma HDL-C, apoE and apoA-I levels compared to controls. Analyses of aortic atherosclerosis revealed a 65% decrease in mean aortic lesion area in hABCA1-Tg compared to control mice. These findings demonstrate that steady state overexpression of ABCA1 in vivo beneficially alters the lipid response to a dietary cholesterol challenge leading to markedly reduced atherosclerosis. Our studies provide the first in vivo evidence of an antiatherogenic role for ABCA1. Thus, pharmacological agents that raise ABCA1 expression may reduce atherogenic risk in humans. ABCG1: Cellular localization and trafficking: ABCG1 is a putative polytopic membrane spanning ABC half-transporter that plays a role in intracellular sterol trafficking. Our previous studies established that adenovirus-mediated hepatic ABCG1 overexpression decreased plasma HDL (20%), increased hepatic cholesterol uptake (1.7-fold), and also increased biliary sterol and phospholipid secretion (2-fold). In addition, ABCG1 expression is transcriptionally regulated by cellular sterol levels. The cellular location, trafficking and molecular mechanism of action of ABCG1 have been controversial. We have expressed a chimeric ABCG1-GFP protein in human HeLa cells to characterize its cellular distribution and possible cellular site(s) of function. HeLa (Tet-off) cells (Clontech, PaloAlto, CA) were co-transfected with EXGen 500 (MBI, Fermentis) using the expression plasmids pTRE2-ABCG1-GFP (pTRE2, Clontech, Palo Alto, CA), encoding a chimeric ABCG1-GFP protein, and ptK-Hyg (Clontech, Palo Alto, CA). In contrast to ABCA1-GFP stably transfected cells, apoA-I did not increase cellular sterol efflux from ABCG1-GFP stably transfected HeLa cells. Confocal laser scanning and time-lapse video microscopy revealed that ABCG1-GFP localized both to the plasma membrane as well as to endocytic vesicles. These findings demonstrate that ABCG1 does not modulate apo-A-I mediated efflux in the stable transfected cell line expressing a functional ABCG1-linked transporter. ABCG1 is present both in the plasma membrane and intracellular late endocytic vesicles. Based on these results, the function of ABCG1 in intracellular sterol trafficking may involve the cycling of ABCG1 between the cell surface and endocytic compartments.
