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Papers In Press, published online ahead of print June 1, 2005
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UT Southwestern Medical Center, Dallas, TX 75390-9052
Corresponding Author: jonathan.cohen{at}utsouthwestern.edu
The major pathway for removal of cholesterol from the body is via secretion into the bile. Three members of the ATP binding cassette (ABC) family, ABCG5 (G5), ABCG8 (G8), and ABCB4 (MDR2), are required for efficient biliary export of sterols. Here we examined the interdependence of these three ABC transporters for biliary sterol secretion. Biliary lipid levels in mice expressing no MDR2 (Mdr2-/- mice) were compared to those of Mdr2-/- mice expressing 14 copies of a human (h) G5 and hG8 transgene (Mdr2-/- ;hG5G8Tg mice). Mdr2-/- mice had only trace amounts of biliary cholesterol and phospholipids. The Mdr2-/- ;hG5G8Tg mice had biliary cholesterol levels as low as those of Mdr2-/- mice. Thus, MDR2 expression is required for G5G8-mediated biliary sterol secretion. To determine if the reduction in fractional absorption of dietary sterols associated with G5G8 over-expression is secondary to the associated increase in biliary cholesterol, we compared the fractional absorption of sterols in the Mdr2-/- ;hG5G8Tg and hG5G8Tg animals. Inactivation of MDR2 markedly attenuated the reduction in fractional sterol absorption associated with G5G8 overexpression. These results are consistent with the notion that increased biliary cholesterol secretion contributes to the reduction in fractional sterol absorption associated with G5G8 overexpression.
Revised on May 11, 2005
Accepted on May 20, 2005
ABCG5 and ABCG8 require MDR2 for secretion of cholesterol into bile
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