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

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

doi:10.1371/journal.pone.0104449

Abstract

Background & AimsLiver 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 & ResultsWe 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 PPARδ agonist GW501516 reduces the proliferative potential of hepatoma cells.ConclusionsOur 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.

Highlights

The liver is a major player in the modulation of lipid and glucose metabolism, xenobiotic detoxification, and is responsible for serum protein synthesis
Our data suggest that Nuclear receptors (NRs) 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
Changes in nuclear receptor transcriptome during Liver regeneration (LR) In order to depict the changes in the NRs transcriptome of the proliferating liver, we performed a two-third partial hepatectomy in wild-type mice

Summary

Introduction

The liver is a major player in the modulation of lipid and glucose metabolism, xenobiotic detoxification, and is responsible for serum protein synthesis. After PH, 95% of the normally quiescent hepatocytes rapidly enter in the S phase of the cell cycle becoming able to replicate. This so called ‘‘priming phase’’ is mostly driven by inflammatory pathways (interleukin-6, IL-6; tumor necrosis factor alpha, TNFa; nuclear Factor-kB, NF-kB; signal transducer and activator of transcription 3, STAT-3; activator protein 1, AP-1; mitogen-activated protein kinase, MAPK), while the ‘‘proliferative phase’’, during which hepatocytes proliferate restoring their original number, is under the control of several growth factors and, at intracellular level, of the Rb family member p107 and cyclins A, D, and E [2,7,8,9]. Nuclear receptors (NRs) are key players in the control of cellular functions, being ideal modulators of hepatic proliferation and carcinogenesis

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