Neuron-derived orphan receptor 1 promotes proliferation of quiescent hepatocytes

Michele Vacca, Stefania Murzilli, Lorena Salvatore, Giuseppe Di Tullio, Andria D'Orazio, Giuseppe Lo Sasso, Giusi Graziano, Massimo Pinzani, Marcello Chieppa, Renato Mariani-Costantini, Giuseppe Palasciano, Antonio Moschetta

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Background & Aims: 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-1small 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-1small 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.

Original languageEnglish (US)
Pages (from-to)1518-1529.e3
JournalGastroenterology
Volume144
Issue number7
DOIs
StatePublished - Jun 2013

Keywords

  • Liver Growth
  • Metabolism
  • Nuclear Receptors
  • Surgery

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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    Vacca, M., Murzilli, S., Salvatore, L., Di Tullio, G., D'Orazio, A., Lo Sasso, G., Graziano, G., Pinzani, M., Chieppa, M., Mariani-Costantini, R., Palasciano, G., & Moschetta, A. (2013). Neuron-derived orphan receptor 1 promotes proliferation of quiescent hepatocytes. Gastroenterology, 144(7), 1518-1529.e3. https://doi.org/10.1053/j.gastro.2013.02.027