Clustering Nuclear Receptors in Liver Regeneration Identifies Candidate Modulators of Hepatocyte Proliferation and Hepatocarcinoma

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 RevErb alpha and RevErb beta, 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, Tr alpha; farsenoid X receptor beta, Fxr beta; Ppar delta) as best discriminators of the proliferating status. To validate our approach, we further studied PPAR delta role in modulating hepatic proliferation. We first confirmed the suppression of PPAR delta both in LR and human hepatocellular carcinoma at protein level, and then demonstrated that PPAR delta 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.