ABCG5 and ABCG8 require MDR2 for secretion of cholesterol into bile

Silvia Langheim,Liqing Yu,Klaus Von Bergmann,Dieter Lütjohann,Fang Xu,Helen H Hobbs,Jonathan C Cohen

doi:10.1194/jlr.m500115-jlr200

Abstract

The major pathway for the 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 the 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 with those of Mdr2-/- mice expressing 14 copies of a human G5 (hG5) 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 whether the reduction in fractional absorption of dietary sterols associated with G5G8 overexpression is secondary to the associated increase in biliary cholesterol, we compared the fractional absorption of sterols in 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.

Highlights

The major pathway for the removal of cholesterol from the body is via secretion into the bile
To determine whether high-level ATP binding cassette transporter G5 (G5) and ATP binding cassette transporter G8 (G8) expression, which is associated with a dramatic increase in biliary cholesterol levels in wild-type mice [8], can overcome the defect in biliary cholesterol secretion, we developed Mdr2Ϫ/Ϫ mice expressing a human G5 and G8 transgene (Mdr2Ϫ/Ϫ;hG5G8Tg)
In mice with normal ATP binding cassette transporter B4 (MDR2) activity, overexpression of G5 and G8 is associated with a marked reduction in the fractional absorption of neutral sterols, a 5-fold increase in biliary cholesterol levels, and a dramatic reduction in plasma levels of the major plant sterols campesterol and sitosterol [8]

Summary

Introduction

The major pathway for the removal of cholesterol from the body is via secretion into the bile. Biliary lipid levels in mice expressing no MDR2 (Mdr2؊/؊ mice) were compared with those of Mdr2؊/؊ mice expressing 14 copies of a human G5 (hG5) and hG8 transgene (Mdr2؊/؊;hG5G8Tg mice). MDR2 expression is required for G5G8-mediated biliary sterol secretion. To determine whether the reduction in fractional absorption of dietary sterols associated with G5G8 overexpression is secondary to the associated increase in biliary cholesterol, we compared the fractional absorption of sterols in 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.—Langheim, S., L. ABCG5 and ABCG8 require MDR2 for secretion of cholesterol into bile.

Methods

Results

Conclusion