Activation of the liver X receptor protects against hepatic injury in endotoxemia by suppressing Kupffer cell activation.
Recent reports have demonstrated that liver X receptors (LXRs) of the nuclear receptor family have anti-inflammatory effects on macrophages. Here we examine whether activation of LXR by the synthetic agonist GW3965 can ameliorate the liver injury/dysfunction caused by endotoxins in the rat. Male Wistar rats received GW3965 (0.3 mg/kg) or vehicle (50% dimethyl sulfoxide) 30 min before coadministration of lipopolysaccharide (LPS, 5 mg/kg i.v.) and peptidoglycan (1 mg/kg i.v.). Treatment with GW3965 attenuated the increase in the plasma levels of alanine aminotransferase and bilirubin (markers of liver injury/dysfunction) as well as the focal hepatocyte necrosis (histology) caused by coadministration of LPS and peptidoglycan. This protective effect of GW3965 treatment was associated with reduced infiltration of mast cells in the liver (histopathology) and reduced gene expression of the chemokines eotaxins 1 and 2, whereas MIP-2 mRNA levels were not affected. Plasma levels of tumor necrosis factor alpha and prostaglandin E2 were significantly attenuated by GW3965, whereas plasma interleukins 6 and 10 were not altered. High expression of LXRalpha mRNA was observed in Kupffer cell cultures, suggesting that Kupffer cells are targets of GW3965. Subsequent in vitro studies in Kupffer cells demonstrated that exposure to GW3965 attenuated the LPS-induced release of tumor necrosis factor alpha and prostaglandin E2 in a dose-dependent manner. In conclusion, this study demonstrates that activation of LXR by GW3965 protects against liver injury and dysfunction in a rat model of endotoxemia, in part by exerting an anti-inflammatory effect on Kupffer cells.
Wang
Yun Yong
YY
University of Oslo, Faculty Division Rikshospitalet, Institute for Surgical Research, Sognsvannsveien 20, 0027 Oslo, Norway.
Dahle
Maria K
MK
Agren
Joanna
J
Myhre
Anders E
AE
Reinholt
Finn P
FP
Foster
Simon J
SJ
Collins
Jon L
JL
Thiemermann
Christoph
C
Aasen
Ansgar O
AO
Wang
Jacob E
JE
D000818:Animals; D001565:Benzoates / Q000008:administration & dosage*; D001596:Benzylamines / Q000008:administration & dosage*; D001798:Blood Proteins / Q000032:analysis; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D015232:Dinoprostone / Q000097:blood; D004305:Dose-Response Relationship, Drug; D019446:Endotoxemia / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D048550:Hepatic Insufficiency / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007728:Kupffer Cells / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity; D008099:Liver / Q000293:injuries / Q000473:pathology; D000071518:Liver X Receptors; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology; D057093:Orphan Nuclear Receptors; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism
D001565:Benzoates; D001596:Benzylamines; D001798:Blood Proteins; D004268:DNA-Binding Proteins; C473027:GW 3965; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D015232:Dinoprostone