Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
The nuclear receptors CAR and PXR are highly expressed in the liver and activated by numerous chemicals, such as drugs, food ingredients, and pesticides. Since CAR and PXR play important roles in various physiological events in our body, their activation by chemicals has been extensively studied in the field of drug metabolism, chemical toxicity, and food safety. We have been investigating the regulation of hepatocyte proliferation and liver cancer promotion by CAR and PXR.
Chemical activation of CAR induces hepatocyte proliferation and liver carcinogenesis in rodents. However, its precise mechanisms are still unknown. Besides, it is well known that CAR-dependent hepatocyte proliferation and liver carcinogenesis are not observed in humans. We have been investigating the molecular mechanism for the CAR-mediated hepatocyte proliferation and its species difference. We have recently found that YAP, which is known as a liver cancer inducer, plays a key role in the CAR-induced hepatocyte proliferation in rodents.
It remains unclear whether PXR activation drives liver cancer or not, although CAR and PXR are structurally and functionally similar nuclear receptors. We thus investigated the influence of PXR activation on liver carcinogenesis and found that PXR activation alone promotes neither hepatocyte proliferation nor liver cancer but it enhances the proliferation induced by various stimuli, such as CAR activation. Mechanistic analyses have revealed that PXR interferes with the FOXO3 transcription factor to reduce the expression of cell cycle suppressor genes, and increases hepatocytes’ sensitivity to various types of proliferating stimuli.
In this lecture, I will introduce our recent progress on CAR- and PXR-dependent regulations of hepatocyte proliferation.
