The nuclear receptor, peroxisome proliferator-activated receptor- (PPAR-), is anti-inflammatory in animal models of endotoxemia. We have shown that PPAR- gene expression is downregulated in macrophages after lipopolysaccharide (LPS) stimulation. However, it remains unknown whether hepatic PPAR- is altered in sepsis and, if so, whether LPS directly downregulates PPAR-. To study this, rats were subjected to sepsis by cecal ligation and puncture (CLP). Hepatic tissues were harvested at 5, 10 and 20 h after CLP. PPAR- gene expression and protein levels were determined by RT-PCR and Western blot, respectively. The results showed that PPAR- gene expression decreased at 10 and 20 h and its proteins levels were reduced at 20 h after CLP. To determine the direct effect of LPS on PPAR- downregulation, LPS binding agent polymyxin B (PMB) was administered intramuscularly after CLP. Administration of PMB significantly reduced plasma levels of endotoxin and partially attenuated TNF- gene expression in hepatic tissues, but it did not prevent the downregulation of PPAR- expression. We found that circulating levels of TNF- still remained significantly elevated in PMB-treated septic animals. We therefore hypothesize that TNF- directly decreases PPAR- expression. To investigate this, Kupffer cells were isolated from normal rats and stimulated with LPS or TNF-. Both LPS and TNF- significantly attenuated PPAR- gene expression in Kupffer cells. The downregulatory effect of LPS on PPAR- was blocked by adding TNF- neutralizing antibodies in the culture. We therefore conclude that LPS downregulates Kupffer cell PPAR- expression in sepsis via the increase in TNF- release.