Selective sterol accumulation in ABCG5/ABCG8-deficient mice

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

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

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 (GSG8-/-) mice. The total sterol content of liver and plasma was similar in G5G8-/- mice and wild-type animals despite an ∼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, Δ22, and 5α-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.

Original languageEnglish (US)
Pages (from-to)301-307
Number of pages7
JournalJournal of Lipid Research
Volume45
Issue number2
DOIs
StatePublished - Feb 2004

Fingerprint

Sterols
Cholesterol
Liver
Bile
Plasmas
Animals
Cholestanol
Stigmasterol
Phytosterols
Wild Animals
ATP-Binding Cassette Transporters
Biosynthetic Pathways
Intestinal Absorption
Rare Diseases
Machinery
Brain
Genes
Tissue
Messenger RNA
Mutation

Keywords

  • Biliary secretion
  • Brain
  • Plant sterols
  • Sitosterolemia

ASJC Scopus subject areas

  • Endocrinology

Cite this

Selective sterol accumulation in ABCG5/ABCG8-deficient mice. / Yu, Liqing; Von Bergmann, Klaus; Lutjohann, Dieter; Hobbs, Helen H.; Cohen, Jonathan C.

In: Journal of Lipid Research, Vol. 45, No. 2, 02.2004, p. 301-307.

Research output: Contribution to journalArticle

Yu, Liqing ; Von Bergmann, Klaus ; Lutjohann, Dieter ; Hobbs, Helen H. ; Cohen, Jonathan C. / Selective sterol accumulation in ABCG5/ABCG8-deficient mice. In: Journal of Lipid Research. 2004 ; Vol. 45, No. 2. pp. 301-307.
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