Liver damage resulting from chronic ethanol consumption is also caused by inflammatory processes. As previously reported, in alcoholics increased LPS levels and altered metabolism induce inflammation, worsening alcoholic liver disease, and Kupffer cells are more sensitive to LPS due to increased expression of Toll-like receptor 4 [23]. In the negative acute hepatic phase response, LPS induces a downregulation of lipid metabolism associated with increased serum triglyceride levels and reduced lipid β-oxidation. These effects appear to be mediated by a reduction of nuclear receptors expression mediated by TNF-α and IL-1 but not IL-6 [120]. RXRα expression is lower in LPS negative acute hepatic phase response [101] and HepG2 IL-1 β-cells showed a marked decline in RAR/RXR binding to the Ntcp gene that regulates bile flow [121]. The alteration of RXR pathways is associated with changes in its subcellular localization characterized by increased cytoplasmic and reduced nuclear levels [122]. The nuclear residence of RXRα is maintained inhibiting c-jun N-terminal kinase or CRM-1-mediated nuclear export, while IL-1 increases the proteasome mediated RXR degradation [123].
