Effects of Oxygen Concentration on the Expression of an Antioxidant Gene in HepG2

Sone, Yasuko; Kudo, Yasuko; Oba, Rieko; Otsuka, Yuzuru

doi:10.1271/bbb.90837

Cited by 1 publication

(1 citation statement)

References 27 publications

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“…Wnt signaling is not the only driving factor of liver zonation . Altering the oxygen concentration has been successfully shown to modulate the zonation phenotype as well. − Monitoring cellular oxygen concentration, however, has been shown to regulate 5 times fewer zonated genes than Wnt signaling in vivo . Nevertheless, we hypothesize that manipulating Wnt signaling in concert with oxygen would potentially improve the zonated phenotype of cultured hepatocytes, as in vivo data show a synergistic effect of Hif1α, the main effector of hypoxic signaling, and β-catenin in creating liver zonation .…”

Section: Discussionmentioning

confidence: 92%

Controlled Functional Zonation of Hepatocytes In Vitro by Engineering of Wnt Signaling

et al. 2020

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Key liver functions, including protein synthesis, carbohydrate metabolism, and detoxification, are performed by specific populations of hepatocytes that are defined by their relative positions within the liver lobules. On a molecular level, the functional heterogeneity with periportal and pericentral phenotypes, so-called metabolic liver zonation, is mainly established by a gradient of canonical Wnt signaling activity. Since the relevant physiological cues are missing in in vitro liver models, they fail to reflect the functional heterogeneity and thus lack many liver functions. We synthetically re-engineered Wnt signaling in murine and human hepatocytes using a doxycycline-dependent cassette for externally controlled digital expression of stabilized β-catenin. Thereby, we achieved adjustable mosaic-like activation of Wnt signaling in in vitro-cultured hepatocytes that was resistant to negative-feedback loops. This allowed the establishment of long-term-stable periportal-like and pericentral-like phenotypes that mimic the heterogeneity observed in vivo. The in vitro-zonated hepatocytes show differential expression of drug-metabolizing enzymes and associated differential toxicity and higher levels of autophagy. Furthermore, recombinant adeno-associated virus and hepatitis C virus preferentially transduce the pericentral-like zonation phenotype, suggesting a bias of these viruses that has been unappreciated to date. These tightly controlled in vivo-like systems will be important for studies evaluating aspects of liver zonation and for the assessment of drug toxicity for mouse and man.

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