Aryl Hydrocarbon Receptor Promotes Liver Polyploidization and Inhibits PI3K, ERK, and Wnt/β-Catenin Signaling

Summary: Aryl hydrocarbon receptor (AhR) deficiency alters tissue homeostasis. However, how AhR regulates organ maturation and differentiation remains mostly unknown. Liver differentiation entails a polyploidization process fundamental for cell growth, metabolism, and stress responses. Here, we repo...

Full description

Bibliographic Details
Main Authors: Nuria Moreno-Marín, Jaime M. Merino, Alberto Alvarez-Barrientos, Daxeshkumar P. Patel, Shogo Takahashi, José M. González-Sancho, Pablo Gandolfo, Rosa M. Rios, Alberto Muñoz, Frank J. Gonzalez, Pedro M. Fernández-Salguero
Format: Article
Language:English
Published: Elsevier 2018-06-01
Series:iScience
Online Access:http://www.sciencedirect.com/science/article/pii/S2589004218300610
Description
Summary:Summary: Aryl hydrocarbon receptor (AhR) deficiency alters tissue homeostasis. However, how AhR regulates organ maturation and differentiation remains mostly unknown. Liver differentiation entails a polyploidization process fundamental for cell growth, metabolism, and stress responses. Here, we report that AhR regulates polyploidization during the preweaning-to-adult mouse liver maturation. Preweaning AhR-null (AhR−/−) livers had smaller hepatocytes, hypercellularity, altered cell cycle regulation, and enhanced proliferation. Those phenotypes persisted in adult AhR−/− mice and correlated with compromised polyploidy, predominance of diploid hepatocytes, and enlarged centrosomes. Phosphatidylinositol-3-phosphate kinase (PI3K), extracellular signal-regulated kinase (ERK), and Wnt/β-catenin signaling remained upregulated from preweaning to adult AhR-null liver, likely increasing mammalian target of rapamycin (mTOR) activation. Metabolomics revealed the deregulation of mitochondrial oxidative phosphorylation intermediates succinate and fumarate in AhR−/− liver. Consistently, PI3K, ERK, and Wnt/β-catenin inhibition partially rescued polyploidy in AhR−/− mice. Thus, AhR may integrate survival, proliferation, and metabolism for liver polyploidization. Since tumor cells tend to be polyploid, AhR modulation could have therapeutic value in the liver. : Developmental Biology; Cancer Systems Biology; Metabolomics Subject Areas: Developmental Biology, Cancer Systems Biology, Metabolomics
ISSN:2589-0042