Nature Communications · 2016 · 86 citations · 33 references
Life SciencesCell BiologyMolecular BiologyGene ExpressionSignal TransductionTranscriptional RegulationChronic Liver DiseaseFibrosisHepatic FibrosisHepatic PathologyHepatic PathophysiologyLiver Disease3' Untranslated Region RegulationActivated Hepatic Stellate CellsHepatic Stellate Cell BiologyHepatic Stellate Cell FunctionInterferon Gamma ProductionLiver Fibrosis ProgressionLiver Stellate Cell ActivationP38 Mitogen-activated Protein Kinase Signaling
Excessive activation of hepatic stellate cells (HSCs) is a key step in liver fibrogenesis. Here we report that CUG-binding protein 1 (CUGBP1) expression is elevated in HSCs and positively correlates with liver fibrosis severity in human liver biopsies. Transforming growth factor-beta (TGF-β) selectively increases CUGBP1 expression in cultured HSCs in a p38 mitogen-activated protein kinase (MAPK)-dependent manner. Knockdown of CUGBP1 inhibits alpha smooth muscle actin (α-SMA) expression and promotes interferon gamma (IFN-γ) production in HSCs in vitro. We further show that CUGBP1 specifically binds to the 3' untranslated region (UTR) of human IFN-γ mRNA and promotes its decay. In mice, knockdown of CUGBP1 alleviates, whereas its overexpression exacerbates, bile duct ligation (BDL)-induced hepatic fibrosis. Therefore, CUGBP1-mediated IFN-γ mRNA decay is a key event for profibrotic TGF-β-dependent activation of HSCs, and inhibiting CUGBP1 to promote IFN-γ signalling in activated HSCs could be a novel strategy to treat liver fibrosis.
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