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Nrf2 induces lipocyte phenotype via a SOCS3-dependent negative feedback loop on JAK2/STAT3 signaling in hepatic stellate cells.
Int Immunopharmacol. 2017 Aug; 49:203-211.II

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Therapeutic material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Therapeutic material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Therapeutic material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Therapeutic material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.Department of Pathology, School of Medicine, Saint Louis University, St Louis, MO, USA.Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Therapeutic material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China; Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China. Electronic address: nytws@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28601022

Citation

Lu, Chunfeng, et al. "Nrf2 Induces Lipocyte Phenotype Via a SOCS3-dependent Negative Feedback Loop On JAK2/STAT3 Signaling in Hepatic Stellate Cells." International Immunopharmacology, vol. 49, 2017, pp. 203-211.
Lu C, Xu W, Shao J, et al. Nrf2 induces lipocyte phenotype via a SOCS3-dependent negative feedback loop on JAK2/STAT3 signaling in hepatic stellate cells. Int Immunopharmacol. 2017;49:203-211.
Lu, C., Xu, W., Shao, J., Zhang, F., Chen, A., & Zheng, S. (2017). Nrf2 induces lipocyte phenotype via a SOCS3-dependent negative feedback loop on JAK2/STAT3 signaling in hepatic stellate cells. International Immunopharmacology, 49, 203-211. https://doi.org/10.1016/j.intimp.2017.06.001
Lu C, et al. Nrf2 Induces Lipocyte Phenotype Via a SOCS3-dependent Negative Feedback Loop On JAK2/STAT3 Signaling in Hepatic Stellate Cells. Int Immunopharmacol. 2017;49:203-211. PubMed PMID: 28601022.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nrf2 induces lipocyte phenotype via a SOCS3-dependent negative feedback loop on JAK2/STAT3 signaling in hepatic stellate cells. AU - Lu,Chunfeng, AU - Xu,Wenxuan, AU - Shao,Jiangjuan, AU - Zhang,Feng, AU - Chen,Anping, AU - Zheng,Shizhong, Y1 - 2017/06/08/ PY - 2017/04/04/received PY - 2017/05/18/revised PY - 2017/06/01/accepted PY - 2017/6/11/pubmed PY - 2018/5/2/medline PY - 2017/6/11/entrez KW - Hepatic fibrosis KW - Hepatic stellate cells KW - JAK2/STAT3 KW - Lipocyte phenotype KW - Nrf2 KW - SOCS3 SP - 203 EP - 211 JF - International immunopharmacology JO - Int Immunopharmacol VL - 49 N2 - 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. SN - 1878-1705 UR - https://www.unboundmedicine.com/medline/citation/28601022/Nrf2_induces_lipocyte_phenotype_via_a_SOCS3_dependent_negative_feedback_loop_on_JAK2/STAT3_signaling_in_hepatic_stellate_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1567-5769(17)30223-0 DB - PRIME DP - Unbound Medicine ER -