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Journal of Lipid Research, Vol. 45, 301-307, February 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology
* McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
** Departments of Molecular Genetics and Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046
Department of Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany
1 To whom correspondence should be addressed. e-mail: 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 noncholesterol 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 an 
30-fold increase in noncholesterol 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 noncholesterol sterols by ABCG5 and ABCG8 prevents the 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.
Supplementary key words plant sterols • biliary secretion • brain • sitosterolemia
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