Rosiglitazone attenuates suppression of RXRalpha-dependent gene expression in inflamed liver.
OBJECTIVE
A recently determined target of lipopolysaccharide (LPS) and cytokine signaling in liver is the central Type II nuclear receptor (NR) heterodimer partner, retinoid X receptor alpha (RXRalpha). We sought to determine if Rosiglitazone (Rosi), a peroxisome proliferator activated receptor gamma (PPARgamma) agonist with anti-inflammatory properties, can attenuate LPS and cytokine-induced molecular suppression of RXRalpha-regulated genes.


METHODS
In vivo, mice were gavage-fed Rosi for 3 days, prior to intraperitoneal injection of LPS, followed by harvest of liver and serum. In vitro, HepG2 cells were treated with IL-1beta, +/- short-term Rosi pretreatment. RNA was analyzed by quantitative RT-PCR, while nuclear and cytoplasmic proteins were analyzed by immunoblotting and gel shifts.


RESULTS
Rosi attenuated LPS-mediated suppression of RNA levels of several Type II NR-regulated genes, including bile acid transporters and the major drug metabolizing enzyme, Cyp3a11, without affecting cytokine expression, suggesting a novel, direct anti-inflammatory effect in hepatocytes. Rosi suppressed the inflammation-induced nuclear export of RXRalpha, in both LPS-injected mice and IL-1beta-treated HepG2 cells, leading to maintenance of nuclear RXRalpha levels and heterodimer binding activity.


CONCLUSIONS
Rosi directly attenuates the suppressive effects of inflammation-induced cell signaling on nuclear RXRalpha levels in liver.
Ghose
Romi
R
Texas Children's Liver Center/Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Mulder
Jaap
J
von Furstenberg
Richard J
RJ
Thevananther
Sundararajah
S
Kuipers
Folkert
F
Karpen
Saul J
SJ
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001483:Base Sequence; D016207:Cytokines / Q000096:biosynthesis; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects*; D006520:Hepatitis, Animal / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*
D016207:Cytokines; D017931:DNA Primers; D008070:Lipopolysaccharides; D047495:PPAR gamma; D047490:Retinoid X Receptor alpha; D045162:Thiazolidinediones; D000077154:Rosiglitazone