Nrf2 induces lipocyte phenotype via a SOCS3-dependent negative feedback loop on JAK2/STAT3 signaling in hepatic stellate cells

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Hepatic stellate cells (HSCs) are universally acknowledged to play a core role in the pathogenesis of hepatic fibrosis. HSCs when activated are characterized by dramatic loss of intracellular lipid droplets. Accumulative evidence has suggested that recovery of lipid droplets could suppress HSC activation. However, the underlying molecular mechanisms still remain largely unclear. In this study, we found that the expression and activity of nuclear factor (erythroid-derived 2) - like 2 (Nrf2) were decreased in activated HSCs and negatively correlated with hepatic fibrosis severity in human liver specimens. Nrf2 overexpression, in contrast to Nrf2 deficiency, induced the accumulation of lipid droplets via decreasing the expression of lipolytic gene peroxisome proliferator-activated receptor alpha (PPARα) and increasing the expression of genes involved in lipogenesis and retinoic acid responsiveness, including CCAAT/enhancer-binding protein alpha, PPARγ, retinoid X receptor alpha, and retinoic acid receptor beta. Consequently, HSCs regained its lipocyte phenotype and expressed reduced alpha-smooth muscle actin and collagen type I. Consistently, disruption of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling by AG490 or Stattic could also induce lipocyte phenotype. Noticeably, Nrf2 overexpression by a genetic approach disrupted JAK2/STAT3 signaling and increased the expression of suppressor of cytokine signaling 3 (SOCS3) but not other protein inhibitors of activated STATs. Gain- or loss-of function of SOCS3 revealed that Nrf2 inhibited JAK2/STAT3 signaling via inducing SOCS3 expression. In conclusion, Nrf2 activation induced lipocyte phenotype in HSCs via enhancing SOCS3-dependent feedback inhibition on JAK2/STAT3 cascade. Nrf2 could be a target molecule for antifibrotic strategy.HighlightsHepatic fibrosis stage negatively correlates with Nrf2 expression in HSCs.Lipocyte phenotype in activated HSCs is induced by Nrf2.Lipid droplets in HSCs are restored by blockade of JAK2/STAT3 pathway.Interaction between Nrf2 and JAK2/STAT3 pathway is based on SOCS3 signal.

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