Identification of novel functions for the ATP binding cassette transporters G1 and G4 during development and ageing

ABCG1 and ABCG4 are members of the ATP binding cassette (ABC) transporter family of proteins that utilize ATP hydrolysis to translocate substrates across cellular membranes. ABCG1 and ABCG4 are half transporters that mediate efflux of cellular cholesterol to specific acceptors, such as lipid-rich HDL. While ABCG1 is widely expressed in many tissues, ABCG4 expression is restricted to the brain and the eye. Herein, we describe studies to further understand the role of these two ABC transporters in the CNS, arterial wall and during development.;Analysis of embryos obtained from Abcg1-/-LacZ and Abcg4-/-LacZ knock-in mice showed that ABCG4 is highly but transiently expressed both in hematopoietic cells of the fetal liver and in the intestine. In contrast, ABCG1 is expressed in hepatic and intestinal macrophages both during development and in the adult. We show that ABCG1 and ABCG4 are both highly expressed in the embryonic eye and developing CNS and that this expression persists into the adulthood. Although the loss of both ABCG1 and ABCG4 in the retina resulted in the accumulation of lathosterol we failed to observe any functional changes by electroretinography. Brains of Abcg1-/-Abcg4-/- mice accumulate numerous oxysterols that led to the induction of genes involved in cholesterol efflux and to the repression of genes involved in cholesterol synthesis. Finally, after subjecting Abcg1-/-Abcg4 -/- mice to a battery of behavioral tests, we identified a general deficit in associative fear memory in Abcg4-/- mice. We conclude that the loss of ABCG1 and/or ABCG4 from the CNS result in altered cholesterol homeostasis that leads to changes in behavior.;In the second study we generated Abcg1-/-Apoe -/- mice in order to investigate the role of ABCG1 in atherosclerosis. We performed a bone marrow transplantation experiment utilizing donor cells from Abcg1-/-Apoe-/- and Apoe-/- mice and recipient hyperlipidemic Apoe-/- mice. Analysis of aortic root lesions showed that mice that received bone marrow cells from Abcg1-/-Apoe -/- mice had a decrease in atherosclerotic lesions. We show that these same mice exhibited an increase in apoptosis in the aortic root lesions as well as a decrease in lesion calcification. Studies are currently underway to further define the mechanism underlying the decrease in atherosclerotic lesions due to the loss of ABCG1.