LPS/IL-1 Mediated Inhibition of RXR Function

Endotoxin lipopolysaccharide (LPS), a major component of the outer membrane of Gram-negative bacteria, potently stimulates host innate immune response. LPS binds the CD14/TRL4/MD2 receptor complex, which promotes the secretion of pro-inflammatory cytokines (IL-1, TNFα) in different cell types, but especially in macrophages. Infection, inflammation and injury down-regulate the expression of hepatic genes involved in a variety of physiological processes, collectively known as the negative hepatic acute phase response (APR). Many of the repressed genes during APR are regulated by the nuclear hormone receptor retinoid X receptor α (RXRα). The retinoid X receptors (RXRs) are nuclear receptors that mediate the biological effects of retinoids by their involvement in retinoic acid-mediated gene activation. RXRα represents the dimerization partner for the type II nuclear receptors. This group includes the liver X receptor (LXR), farnesoid X receptor (FXR), retinoic acid receptor (RAR), constitutive androstane receptor (CAR), pregnane X receptor (PXR) and peroxisome proliferator-activated receptor (PPAR). In response to pro-inflammatory cytokines signaling, RXRα undergoes a JNK-mediated, CRM-1-dependent nuclear export, leading to decreased nuclear RXRα levels and reduced nuclear DNA binding and transcriptional activity. Reduction in the expression of hepatic transport proteins (ABC, OATP, MDR1, NTCP), metabolizing enzymes (CYP, GST, UGT, SOD) and biosynthesis enzymes (CYP7A1) leads to impaired metabolism, transport and/or biosynthesis of lipid, cholesterol, bile acid and xenobiotics.