Neuron-derived orphan receptor 1 promotes proliferation of quiescent hepatocytes.

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 (sh)RNAs (Ad/BLOCK-iT™/Nor-1 shRNA) following partial hepatectomy. RESULTS: Levels ofNor-1mRNA 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 ofNOR-1mRNA, and transcription of its target geneCCND1 and of the NOR-1 subfamily member NUR-77, also increased in human HCC samples, compared with healthy liver tissue. Ad-shRNAs against Nor-1 reduced the hepatocyte proliferation following 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 following partial hepatectomy. Nor-1 and its gene targets are also upregulated in human HCC samples. Nor-1 activates a transcriptional program that induces hepatocyte proliferation independently of inflammatory signaling pathways.