Novel roles of liver X receptors exposed by gene expression profiling in liver and adipose tissue.
Liver X receptor (LXR) alpha and LXRbeta are nuclear oxysterol receptors whose biological function has so far been elucidated only with respect to cholesterol and lipid metabolism. To expose novel biological roles for LXRs, we performed genome-wide gene expression profiling studies in liver and white and brown adipose tissue from wild-type (LXRalpha(+/+)beta(+/+)) and knockout mice (LXRalpha(-/-)beta(-/-)) treated with a synthetic LXR agonist. By an adapted statistical analysis, we detected 319 genes significantly regulated by LXR agonist treatment in wild-type but not in knockout mice, fulfilling most stringent criteria with an overall confidence of 94%. Down-regulation of essential enzymes of gluconeogenesis in liver could point to possible beneficial effects of LXR agonists in diabetes mellitus. LXR agonist treatment also altered expression of genes involved in steroid hormone synthesis and growth hormone receptor signaling, emphasizing a potential impact on endocrine function. Notably, LXR agonist treatment up-regulated CYP4A10 and CYP4A14 together with cytochrome P450 reductase, indicating a possible enhancement of microsomal lipid peroxidation. In conclusion, these gene expression profiling data identify novel areas of regulation by LXRs and provide a highly valuable basis for further research on the biological functions of these nuclear receptors and the pharmacological characteristics of their ligands.
Stulnig
Thomas M
TM
Department of Medical Nutrition and Biosciences, Karolinska Institutet, Huddinge, Sweden. thomas.stulnig@akh-wien.ac.at
Steffensen
Knut R
KR
Gao
Hui
H
Reimers
Mark
M
Dahlman-Wright
Karin
K
Schuster
Gertrud U
GU
Gustafsson
Jan-Ake
JA
D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D004268:DNA-Binding Proteins; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008099:Liver / Q000502:physiology*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear