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

IScience
Nuria Moreno-MarínPedro M Fernández-Salguero

Abstract

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 polyploidi...Continue Reading

Citations

Mar 19, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yasunari MatsuzakaYoshihiro Uesawa
Jan 12, 2019·Science·Andrew WangRuslan Medzhitov
Sep 20, 2019·Toxicological Sciences : an Official Journal of the Society of Toxicology·Jana SvobodováJan Vondráček
Aug 4, 2020·Science Advances·Kalina PaunovskaJames E Dahlman
Jun 3, 2021·Seminars in Immunopathology·Antonella Carambia, Fenja Amrei Schuran
Aug 28, 2021·Cancers·Ana Nacarino-PalmaPedro M Fernández-Salguero

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Methods Mentioned

BETA
fluorescence microscopy
flow cytometry
confocal microscopy
enzyme-linked immunosorbent assay
co-immunoprecipitation

Software Mentioned

ImageJ

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