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.