Nrf2 Enhances Cholangiocyte Expansion in Pten-Deficient Livers

Abstract

Keap1-Nrf2 system plays a central role in the stress response. While Keap1 ubiquitinates Nrf2 for degradation under unstressed conditions, this Keap1 activity is abrogated in response to oxidative or electrophilic stresses, leading to Nrf2 stabilization and coordinated activation of cytoprotective genes. We recently found that nuclear accumulation of Nrf2 is significantly increased by simultaneous deletion of Pten and Keap1, resulting in the stronger activation of Nrf2 target genes. To clarify the impact of the cross talk between the Keap1-Nrf2 and Pten–phosphatidylinositide 3-kinase–Akt pathways on the liver pathophysiology, in this study we have conducted closer analysis of liver-specific Pten::Keap1 double-mutant mice (Pten::Keap1-Alb mice). The Pten::Keap1-Alb mice were lethal by 1 month after birth and displayed severe hepatomegaly with abnormal expansion of ductal structures comprising cholangiocytes in a Nrf2-dependent manner. Long-term observation of Pten::Keap1-Alb::Nrf2^+/− mice revealed that the Nrf2-heterozygous mice survived beyond 1 month but developed polycystic liver fibrosis by 6 months. Gsk3 directing the Keap1-independent degradation of Nrf2 was heavily phosphorylated and consequently inactivated by the double deletion of Pten and Keap1 genes. Thus, liver-specific disruption of Keap1 and Pten augments Nrf2 activity through inactivation of Keap1-dependent and -independent degradation of Nrf2 and establishes the Nrf2-dependent molecular network promoting the hepatomegaly and cholangiocyte expansion.

ACKNOWLEDGMENTS

We thank Eriko Naganuma for assistance with the histological analyses. We also thank the Biomedical Research Core of Tohoku University Graduate School of Medicine for technical support.

This work was supported through funding from JSPS KAKENHI grants 24249015 (M.Y.), 24390075 (H.M.), and 24790307 (K.T.), MEXT KAKENHI grants 23116002 (H.M.) and 25117703 (K.T.), the Gushinkai Foundation (K.T.), the Gonryo Medical Foundation (K.T.), the Naito Foundation (M.Y.), the Takeda Scientific Foundation (H.M. and M.Y.), and the Core Research for Evolutional Science and Technology from the JST (H.M. and M.Y.).