Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma

Michele Vacca, Simona D'Amore, Giusi Graziano, Andria D'Orazio, Marica Cariello, Vittoria Massafra, Lorena Salvatore, Nicola Martelli, Stefania Murzilli, Giuseppe Lo Sasso, Renato Mariani-Costantini, Antonio Moschetta

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Background & Aims: Liver regeneration (LR) is a valuable model for studying mechanisms modulating hepatocyte proliferation. Nuclear receptors (NRs) are key players in the control of cellular functions, being ideal modulators of hepatic proliferation and carcinogenesis. Methods & Results: We used a previously validated RT-qPCR platform to profile modifications in the expression of all 49 members of the NR superfamily in mouse liver during LR. Twenty-nine NR transcripts were significantly modified in their expression during LR, including fatty acid (peroxisome proliferator-activated receptors, PPARs) and oxysterol (liver X receptors, Lxrs) sensors, circadian masters RevErbα and RevErbβ, glucocorticoid receptor (Gr) and constitutive androxane receptor (Car). In order to detect the NRs that better characterize proliferative status vs. proliferating liver, we used the novel Random Forest (RF) analysis to selected a trio of down-regulated NRs (thyroid receptor alpha, Trα; farsenoid X receptor beta, Fxrβ; Pparδ) as best discriminators of the proliferating status. To validate our approach, we further studied PPARδ role in modulating hepatic proliferation. We first confirmed the suppression of PPARδ both in LR and human hepatocellular carcinoma at protein level, and then demonstrated that PPARd agonist GW501516 reduces the proliferative potential of hepatoma cells. Conclusions: Our data suggest that NR transcriptome is modulated in proliferating liver and is a source of biomarkers and bona fide pharmacological targets for the management of liver disease affecting hepatocyte proliferation.

Original languageEnglish (US)
Article numbere104449
JournalPloS one
Volume9
Issue number8
DOIs
StatePublished - Aug 12 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Vacca, M., D'Amore, S., Graziano, G., D'Orazio, A., Cariello, M., Massafra, V., Salvatore, L., Martelli, N., Murzilli, S., Lo Sasso, G., Mariani-Costantini, R., & Moschetta, A. (2014). Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma. PloS one, 9(8), [e104449]. https://doi.org/10.1371/journal.pone.0104449