Activation Mechanism of the Drug-Sensing Nuclear Receptor CAR

Responding to xenotiotics and therapeutic drugs, liver cells coordinately regulate transcription of genes that encode enzymes involved in various metabolisms such as drug detoxification, gluconeogenesis, lipid catabolism and ketogenesis. This transcriptional regulation is controlled by so-called xenobiotic activating or xenosensing nuclear receptors such as the constitutive active/androstane receptor (CAR), a member of the nuclear steroid/thyroid receptor superfamily. It is known that CAR often becomes a determining factor causing various liver diseases in rodents. For instance, phenobarbital activates CAR to promote the development of hepatocellular carcinoma in mice. Diabetes is another disease in which CAR might play a role via its direct interaction with insulin the response transcription factors FoxO1 and FoxA2 and with the glucagon response CREB. These observations suggest that activation of CAR can critically affect human health. However, the molecular mechanism of xenobiotic activation of CAR remains elusive. In particular, unlike other hormone receptors such ERs and GR, CAR can be activated indirectly without binding to xenobiotics, making the mechanism very complex. I will present current results of our investigating to characterize the cellular signal pathways that regulate the CAR activation.