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Title

Aryl hidrocarbon receptor promotes liver polyploidization and inhibits PI3K, ERK and Wnt/beta-catenin signaling

AuthorsMoreno-Marín, Nuria; Merino, Jaime; Alvarez-Barrientos, Alberto; Patel, Daxeshkumar P.; Takahashi, Shogo; González-Sancho, José Manuel ; Gandolfo-Domínguez, Pablo; Ríos, Rosa M. ; Muñoz Terol, Alberto ; González, Frank J.; Fernández-Salguero, Pedro M.
Issue Date29-Jun-2018
PublisherElsevier
CitationiScience 4: 44-63 (2018)
AbstractAryl 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/b-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/b-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
Publisher version (URL)https://doi.org/10.1016/j.isci.2018.05.006
URIhttp://hdl.handle.net/10261/180389
DOI10.1016/j.isci.2018.05.006
E-ISSN2589-0042
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(IIBM) Artículos
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