Repression of Farnesoid X Receptor during the Acute Phase Response

Abstract

The acute phase response is associated with changes in the hepatic expression of genes involved in lipid metabolism. Nuclear hormone receptors that heterodimerize with retinoid X receptor (RXR), such as thyroid receptors, peroxisome proliferator-activated receptors, and liver X receptors, modulate lipid metabolism. We recently demonstrated that these nuclear hormone receptors are repressed during the acute phase response induced by lipopolysaccharide (LPS), consistent with the known decreases in genes that they regulate. In the present study, we show that LPS significantly decreases farnesoid X receptor (FXR) mRNA in mouse liver as early as 8 h after LPS administration, and this decrease was dose-dependent with the half-maximal effect observed at 0.5 g/100 g of body weight. Gel-shift experiments demonstrated that DNA binding activity to an FXR response element (IR1) is significantly reduced by LPS treatment. Supershift experiments demonstrated that the shifted protein-DNA complex contains FXR and RXR. Furthermore, the expression of FXR target genes, SHP and apoCII, were significantly reduced by LPS (70 and 60%, respectively). Also, LPS decreases hepatic LRH expression in mouse, which may explain the reduced expression of CYP7A1 in the face of SHP repression. In Hep3B human hepatoma cells, both tumor necrosis factor (TNF) and interleukin-1 (IL-1) significantly decreased FXR mRNA, whereas IL-6 did not have any effect. TNF and IL-1 also decreased the DNA binding activity to an IR1 response element and the expression of SHP and apoCII. Importantly, TNF and IL-1 almost completely blocked the expression of luciferase activity linked to a FXR response element promoter construct transfected into Hep3B cells. Together with our earlier studies on the repression of RXRs, peroxisome proliferator-activated receptors, LXRs, thyroid receptors, constitutive androstane receptor, and pregnane X receptor, these results suggest that decreases in nuclear hormone receptors are major contributors to the decreased gene expression that occurs in the negative acute phase response.

A Systematic Comparison of the Impact of Inflammatory Signaling on Absorption, Distribution, Metabolism, and Excretion Gene Expression and Activity in Primary Human Hepatocytes and HepaRG Cells

“…Although the downregulating effects of proinflammatory cytokines on CYP3A4 have been repeatedly reported (Jover et al, 2002;Aitken and Morgan, 2007), CYP7A1 has been less well studied in this regard. Downregulation of CYP7A1 may be explained by repression of farnesoid X receptor (Kim et al, 2003).…”

Regulation of Renal Fatty Acid and Cholesterol Metabolism, Inflammation, and Fibrosis in Akita and OVE26 Mice With Type 1 Diabetes

“…Proinflammatory cytokines in the diabetic kidney can also induce downregulation of LXR and FXR (43,44), which would then modulate renal lipid metabolism and add to the complexity of the interactions between nuclear receptors and proinflammatory cytokines in the pathogenesis of diabetic kidney disease.…”

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

“…In our study, mRNA expression levels of iNOS, which in pancolitis is expressed after induction by certain cytokines, microbes, and bacterial products (Kolios et al, 2004), were significantly increased (15-fold), higher than in left-sided colitis (Table 5). During inflammation in the liver, several nuclear hormone receptors are downregulated by inflammatory cytokines, leading to downregulation of their target transporter and detoxification genes (Beigneux et al, 2000;Kim et al, 2003). Our results in pancolitis permit the hypothesis that-as in the liver-markedly increased levels of cytokines during pancolitis mediate disturbances in the expression of regulatory nuclear receptors such as PXR or VDR that consequently are manifest in changes in levels of mRNA of colonic BA transporters, both apical (MRP4, MDR1) and basolateral (MRP3, OSTa/b).…”