An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha.

Nature 1996 Oct;383(6602):728-31

Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, 75235-9050, USA.

Cholesterol and its oxysterol congeners are important constituents of cell membranes and function as intermediates in several crucial biosynthetic pathways. These compounds autoregulate their metabolic fate by end-product repression and activation of downstream catabolism. Although end-product repression by oxysterols is relatively well understood, the mechanism by which these compounds act as positive transcription signalling molecules is unknown. Here we identify a specific group of endogenous oxysterols that activate transcription through the nuclear receptor LXR alpha. Transactivation of LXR alpha by oxysterols occurs at concentrations at which these compounds exist in vivo. The most potent activators also serve as intermediary substrates in the rate-limiting steps of three important metabolic pathways: steroid hormone biosynthesis, bile acid synthesis, and conversion of lanosterol to cholesterol. Our results demonstrate the existence of a nuclear receptor signalling pathway for oxysterols and suggest that LXR alpha may be important as a sensor of cholesterol metabolites.

Download full-text PDF

Source
http://www.nature.com/doifinder/10.1038/383728a0
Publisher Site
http://dx.doi.org/10.1038/383728a0DOI Listing
October 1996
1 Read

Publication Analysis

Top Keywords

lxr alpha
16
nuclear receptor
12
receptor lxr
8
signalling pathway
8
end-product repression
8
unknown identify
4
molecules unknown
4
acid synthesis
4
signalling molecules
4
bile acid
4
identify specific
4
endogenous oxysterols
4
group endogenous
4
biosynthesis bile
4
specific group
4
transcription signalling
4
oxysterols activate
4
well understood
4
oxysterols well
4
conversion lanosterol
4

References

(Supplied by CrossRef)

DW Russell et al.
Cardiovasc. Drugs Ther. 1992

X Wang et al.
Cell 1994

PJ Willy et al.
Genes Dev. 1995

RA Heyman et al.
Cell 1992

MA Harmon et al.
Proc. Natl Acad. Sci. USA 1995

AG Byskov et al.
Nature 1995

AA Kandutsch et al.
Science 1978

AK Dhar et al.
J. Neurochem. 1973

NB Javitt et al.
J. Biol. Chem. 1981

R Dixon et al.
Biochem. Biophys. Res. Commun. 1970

BM Forman et al.
Cell 1995

Similar Publications