Role of Nuclear Receptors PXR and CAR in Xenobiotic-Induced Hepatocyte Proliferation and Chemical Carcinogenesis.

Nuclear receptors pregnane X receptor (PXR) and constitutive active/androstane receptor (CAR) are xenobiotic-responsible transcriptional factors that belong to the same subfamily and are expressed abundantly in the liver. They play crucial roles in various liver functions including xenobiotic disposition and energy metabolism. CAR is also involved in xenobiotic-induced hepatocyte proliferation and hepatocarcinogenesis in rodents. However, there are some open questions on the association between chemical carcinogenesis and these nuclear receptors. These include the molecular mechanism for CAR-mediated hepatocyte proliferation and hepatocarcinogenesis. Another important question is whether PXR is associated with hepatocyte proliferation. We have recently reported a novel and unique function of PXR associated with murine hepatocyte proliferation: PXR activation alone does not induce hepatocyte proliferation but accelerates hepatocyte proliferation induced by various types of stimuli including CAR- or peroxisome proliferator-activated receptor alpha activating compounds, liver injury, and growth factors. We have also reported a role of yes-associated protein (YAP), a transcriptional cofactor controlling organ size and cell growth under the Hippo pathway, in CAR-mediated hepatocyte proliferation in mice. In this review, I will introduce our recent results as well as related studies on the roles of PXR and CAR in xenobiotic-induced hepatocyte proliferation and their molecular mechanisms.