J. Lipid Res. Neurobiology of Lipids (ISSN1683-5506)
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A more recent version of this article appeared on February 1, 2004

Papers In Press, published online ahead of print December 1, 2003
J. Lipid Res., doi:10.1194/jlr.M300377-JLR200
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Submitted on September 5, 2003
Revised on November 5, 2003
Accepted on November 18, 2003

Selective sterol accumulation in ABCG5/ABCG8 deficient mice

Liqing Yu, Klaus von Bergmann, Dieter Lutjohann, Helen H. Hobbs, and Jonathan C. Cohen

UT Southwestern Medical Center, Dallas, TX 75390-9052

Corresponding Author: jonathan.cohen{at}utsouthwestern.edu

The ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 limit intestinal absorption and promote biliary secretion of neutral sterols. Mutations in either gene cause sitosterolemia, a rare recessive disease in which plasma and tissue levels of several neutral sterols are increased to varying degrees. To determine why patients with sitosterolemia preferentially accumulate non-cholesterol sterols, levels of cholesterol and the major plant sterols were compared in plasma, liver, bile, and brain of wild-type and ABCG5/ABCG8 deficient (G5G8-/-) mice. The total sterol content of liver and plasma was similar in G5G8-/- mice and wild-type animals despite a ~30-fold increase in non-cholesterol sterol levels in the knockout animals. The relative enrichment of each sterol in the plasma and liver of G5G8-/- mice (stigmasterol > sitosterol  cholestanol> bassicasterol > campesterol > cholesterol) reflected its relative enrichment in the bile of wild-type mice. These results indicate that 24-alkylated, 22, and 5-reduced sterols are preferentially secreted into bile, and that preferential biliary secretion of non-cholesterol sterols by ABCG5 and ABCG8 prevents accumulation of these sterols in normal animals. The mRNA levels for 13 enzymes in the cholesterol biosynthetic pathway were reduced in the livers of the G5G8-/- mice, despite a 50% reduction in hepatic cholesterol level. Thus the accumulation of sterols other than cholesterol is sensed by the cholesterol regulatory machinery.


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