Regulation of Hepatic Xenosensor Function by HNF4alpha

Abstract

Nuclear receptors including Aryl hydrocarbon Receptor (AhR), Constitutive Androstane Receptor (CAR), Pregnane X Receptor (PXR), and Peroxisome Proliferator-Activated Receptor-alpha (PPAR) function as xenobiotic sensors. Hepatocyte nuclear factor 4alpha (HNF4) is a highly conserved orphan nuclear receptor essential for liver function. We tested the hypothesis that HNF4 is essential for function of these four major xenosensors. Wild-type (WT) and hepatocyte-specific HNF4 knockout (HNF4-KO) mice were treated with the mouse-specific activators of AhR (TCDD, 30 {micro}g/kg), CAR (TCPOBOP, 2.5 {micro}g/g), PXR, (PCN, 100 {micro}g/g), and PPAR (WY-14643, 1 mg/kg). Blood and liver tissue samples were collected to study nuclear receptor activation. TCDD (AhR agonist) treatment did not affect the liver-to-body weight ratio (LW/BW) in either WT or HNF4-KO mice. Further, TCDD activated AhR in both WT and HNF4-KO mice, confirmed by increase in expression of its target genes. TCPOBOP (CAR agonist) significantly increased the LW/BW ratio and CAR target gene expression in WT mice, but not in HNF4-KO mice. PCN (a mouse PXR agonist) significantly increased LW/BW ratio in both WT and HNF4-KO mice however, it failed to induce PXR target genes in HNF4 KO mice. The treatment of WY-14643 (PPAR agonist) increased LW/BW ratio and PPAR target gene expression in WT mice but not in HNF4-KO mice. Together, these data indicate that the function of CAR, PXR, and PPAR but not of AhR was disrupted in HNF4-KO mice. These results demonstrate that HNF4 function is critical for the activation of hepatic xenosensors, which are critical for toxicological responses.