3β,5α,6β-Cholestanetriol and 25-hydroxycholesterol accumulate in ATP-binding cassette transporter G1 (ABCG1)-deficiency.
OBJECTIVE
Oxysterols are oxidized derivatives of sterols that have cytotoxic effects and are potent regulators of diverse cellular functions. Efficient oxysterol removal by the sub-family G member 1 of the ATP-binding cassette transporters (ABCG1) is essential for cell survival and control of cellular processes. However, the specific role of ABCG1 in the transport of various oxysterol species has been not systematically investigated to date. Here, we examined the involvement of ABCG1 in the oxysterol metabolism by studying oxysterol tissue levels in a mouse model of Abcg1-deficiency.


RESULTS
Analysis of lung tissue of Abcg1(-/-) mice on a standard diet revealed that 3β,5α,6β-cholestanetriol (CT) and 25-hydroxycholesterol (HC) accumulated at more than 100-fold higher levels in comparison to wild-type mice. 24S-HC and 27-HC levels were also elevated, but were minor constituents. A radiolabeled assay employing regulable ABCG1-expressing HeLa cell lines revealed that 25-HC export to albumin was dependent on functional ABCG1 expression and could be blocked by an excess of unlabeled 25-HC or 27-HC. In this cell line, 25-HC at low doses triggered mitochondrial membrane potential, and reactive oxygen species production, which are both indirect indicators of cellular energy expenditure.


CONCLUSIONS
Our results suggest that 25-HC and CT are physiologic substrates for ABCG1. Excessive accumulation of these oxysterols may explain the increased rate of cell death and the inflammatory phenotype observed in Abcg1-deficient animals and cells.
Leibniz-Institute for Arteriosclerosis Research at The Westphalian Wilhelms-University, 48149 Muenster, Germany. Electronic address: engeltho@uni-muenster.de.
Thomas
T
Engel
Center for Laboratory Medicine, University Hospital Muenster, 48149 Muenster, Germany.
Manfred
M
Fobker
German Institute of Human Nutrition, Department of Experimental Diabetology, 14558 Potsdam-Rehbruecke, Germany.
Jana
J
Buchmann
Center for Laboratory Medicine, University Hospital Muenster, 48149 Muenster, Germany.
Frank
F
Kannenberg
Leibniz-Institute for Arteriosclerosis Research at The Westphalian Wilhelms-University, 48149 Muenster, Germany.
Stephan
S
Rust
Center for Laboratory Medicine, University Hospital Muenster, 48149 Muenster, Germany.
Jerzy-Roch
JR
Nofer
German Institute of Human Nutrition, Department of Experimental Diabetology, 14558 Potsdam-Rehbruecke, Germany.
Annette
A
Schürmann
Leibniz-Institute for Arteriosclerosis Research at The Westphalian Wilhelms-University, 48149 Muenster, Germany.
Udo
U
Seedorf
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000418:Albumins / Q000737:chemistry; D000818:Animals; D001692:Biological Transport; D016923:Cell Death; D002777:Cholestanols / Q000737:chemistry*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry*; D007249:Inflammation; D008055:Lipids / Q000737:chemistry; D008074:Lipoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism
C419353:ABCG1 protein, human; C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000418:Albumins; D002777:Cholestanols; D006888:Hydroxycholesterols; D008055:Lipids; D008074:Lipoproteins; D017382:Reactive Oxygen Species; C007997:25-hydroxycholesterol
25-Hydroxycholesterol; 3β,5α,6β-Cholestanetriol; ATP-binding cassette transporter, G-subgroup, family member 1 (ABCG1); Inflammation; Lipid efflux; Oxysterols