Activation of the Liver X Receptor Protects Against Hepatic Injury in Endotoxemia by Suppressing Kupffer Cell Activation

Abstract

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.

Genome-Wide Profiling of Liver X Receptor, Retinoid X Receptor, and Peroxisome Proliferator-Activated Receptor α in Mouse Liver Reveals Extensive Sharing of Binding Sites

“…Kupffer cells and the sinusoidal endothelial cells are the most abundant nonhepatocyte cells, representing up to 20% and 15% of all liver cells, respectively (45). PPAR␣ is not detected in isolated rat Kupffer cells (58), whereas LXR␣ is highly expressed in these cells (90). It is therefore possible that a minor portion of the detected LXR binding sites originate from Kupffer cells and these sites would not have overlapping LXR and PPAR␣ binding in hepatocytes.…”

Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis

“…In particular, activation of LXR was found to protect against hepatic injury in an endotoxemia model (Wang et al, 2006c). LXR was shown to attenuate LPS-induced release of TNF-␣ and PGE 2 in a dose-dependent fashion, suggesting that LXR activation may protect against liver injury by suppressing Kupffer cell activation .…”

The synthetic liver X receptor agonist GW3965 reduces tissue factor production and inflammatory responses in human islets in vitro

“…In addition, in vivo and in vitro studies have demonstrated that activation of LXR agonists antagonises inflammatory gene expression in mouse macrophages [10], microglia and astrocytes [11], and human monocytes [12]. In cultured murine and human macrophages the synthetic LXR agonist GW3965 has been shown to reduce cytokine-induced tissue factor (TF) production [13] and we have previously shown that GW3965 dose-dependently attenuated LPS-induced release of TNF-α and prostaglandin E 2 by hepatic Kupffer cells in vitro as well as in vivo [14]. Human islets exposed to human blood trigger an instant blood-mediated inflammatory reaction, characterised by platelet consumption and activation of the coagulation and complement systems, and this activation may impair engraftment after intraportal islet transplantation [15].…”