title: Neuron-derived orphan receptor 1 promotes proliferation of quiescent hepatocytes.
abstract: OBJECTIVE
  Studies of the transcriptional networks that regulate nuclear receptor-mediated proliferation of quiescent hepatocytes could lead to new information about liver growth and hepatoprotective strategies.
  
  
  METHODS
  We used quantitative real-time PCR to analyze expression of neuron-derived orphan receptor 1 (Nor-1) and its target genes during liver regeneration after hepatectomy in mice, and in hepatocellular carcinoma (HCC) samples from patients. We used adenoviral vectors to express Nor-1 in normal liver (Ad/CMV/V5-Nor-1), or reduce its level with small hairpin RNAs (Ad/BLOCK-iT/Nor-1(small hairpin RNA)) after partial hepatectomy.
  
  
  RESULTS
  Levels of Nor-1 messenger RNA and protein, and transcription of Nor-1 target genes (Ccnd1 and Vcam-1), increased during the late priming and proliferative phases of liver regeneration after partial hepatectomy. Levels of NOR-1 messenger RNA and transcription of its target gene CCND1 and of the NOR-1 subfamily member NUR-77 also increased in human HCC samples compared with paired HCC-free tissue. Ad-Nor-1(small hairpin RNA) reduced the hepatocyte proliferation after hepatectomy. Overexpression of Nor-1 in normal livers of mice induced proliferation of quiescent hepatocytes independently of interleukin-6 and tumor necrosis factor-α signaling. In gene expression profile analysis, Nor-1 altered expression of genes involved in the cell cycle, proliferation, and tumorigenesis.
  
  
  CONCLUSIONS
  In mice, the orphan nuclear receptor Nor-1 activates proliferation of quiescent hepatocytes and is required for hepatocyte proliferation after partial hepatectomy. Nor-1 and its gene targets are also up-regulated in human HCC samples. Nor-1 activates a transcriptional program that induces hepatocyte proliferation independently of inflammatory signaling pathways.
authors: Laboratory of Lipid Metabolism and Cancer, Consorzio Mario Negri Sud, Santa Maria Imbaro, Chieti, Italy.
authors: Michele
authors: M
authors: Vacca
authors: Stefania
authors: S
authors: Murzilli
authors: Lorena
authors: L
authors: Salvatore
authors: Giuseppe
authors: G
authors: Di Tullio
authors: Andria
authors: A
authors: D'Orazio
authors: Giuseppe
authors: G
authors: Lo Sasso
authors: Giusi
authors: G
authors: Graziano
authors: Massimo
authors: M
authors: Pinzani
authors: Marcello
authors: M
authors: Chieppa
authors: Renato
authors: R
authors: Mariani-Costantini
authors: Giuseppe
authors: G
authors: Palasciano
authors: Antonio
authors: A
authors: Moschetta
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C490411:Nr4a3 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C479458:OSCP1 protein, human; D012333:RNA, Messenger; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D019010:Vascular Cell Adhesion Molecule-1; D019938:Cyclin D1