could lead to suppression of PPARγ transcriptional activity and promote the release of TNF-α. Indeed, enhanced release of TNF-α in response to acetaldehyde or LPS by Kupffer cells isolated from ethanol-fed rats has been reported [66, 67]. Moreover, in ALD increased TNF-α release by Kupffer cells does occur by LPS stimulation due to increased intestinal permeability (described elsewhere in this review). Circulating LPS binds to LPS binding protein (LBP) [68] which promotes its interaction with the Kupffer cells' CD14 cell-surface receptor. This complex interacts mainly with the toll-like receptor 4 (TLR4), which in turn transduces the down-stream signal through activation of the PCK, MAPK, and NF-kB signalling pathways [69]. Furthermore, ethanol induces the expression of CD14/TLR-4 receptors in kupffer cells, thus “priming” the liver macrophage population to respond to LPS stimulation, and this sensitization was found to depend upon NADPH oxidase mediated-oxidative stress and activation of the NF-kB pathway [22, 70]. TNF-α is also known to downregulate PPARγ function by several mechanisms (see Ye 2008 for a recent review [71]), and LPS treatment was shown to downregulate PPARγ expression in Kupffer cells both in vitro and in an animal model of sepsis through a TNFα -dependent mechanism [72].
