关键词： 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside 5-aza-2′-deoxycytidine 5-azadC AICAR APC BC CK1 CamKII Canonical Wnt signaling pathway DKK DLK1 Delta-like 1 homolog Dickkopf Dvl FLS Fz GFAP Gsk3β HCV HFFs HPCs HSCs Hepatic stellate cell KEGG LEF LOX-1 Liver fibrosis Lrp5/6 MCP-1 MMP MMPCs MeCP2 Myofibroblastic transdifferentiation PCP PDGF PH PITX2c PKC PPAR response element PPRE PRA RA ROK SFRP T-cell specific transcription factors TCF TRAIL UUO Wnt signaling a-SMA a-smooth muscle actin adenomatous polyposis coli baicalin calmodulin kinase II casein kinase 1 disheveled fibroblast-like synoviocytes frizzled glial fibrillary acidic protein glycogen synthase kinase 3β hepatic progenitor cells hepatic stellate cells hepatitis C human foreskin fibroblasts kyoto encyclopedia of genes and genomes lectin-like ox-LDL receptor-1 lipoprotein receptor-related protein 5/6 lymphoid enhancer binding factor matrix metalloproteinase mesoderm-derived multipotent mesenchymal progenitor cells methyl-CpG binding protein 2 monocyte chemotactic protein-1 ox-LDL oxidized low-density lipoprotein paired-like homeodomain transcription factor 2c partial hepatectomy planar cell polarity platelet-derived growth factor polyphenolic rosmarinic acid protein kinase C rheumatoid arthritis rho kinase secreted frizzled-related protein tumor necrosis factor-related apoptosis-inducing ligand unilateral ureteral obstruction

Mesh ： Animals Cell Transdifferentiation / physiology Hepatic Stellate Cells / physiology Humans Intercellular Signaling Peptides and Proteins / pharmacology Liver Cirrhosis / metabolism physiopathology Liver Regeneration / genetics PPAR gamma / metabolism Stem Cells / physiology Wnt Signaling Pathway / drug effects physiology

来  源：   DOI：10.1016/j.biochi.2013.09.003   PDF(Sci-hub)

Abstract：
Liver fibrosis is a common wound-healing response to chronic liver injuries, including alcoholic or drug toxicity, persistent viral infection, and genetic factors. Myofibroblastic transdifferentiation (MTD) is the pivotal event during liver fibrogenesis, and research in the past few years has identified key mediators and molecular mechanisms responsible for MTD of hepatic stellate cells (HSCs). HSCs are undifferentiated cells which play an important role in liver regeneration. Recent evidence demonstrates that HSCs derive from mesoderm and at least in part via septum transversum and mesothelium, and HSCs express markers for different cell types which derive from multipotent mesenchymal progenitors. There is a regulatory commonality between differentiation of adipocytes and that of HSC, and the shift from adipogenic to myogenic or neuronal phenotype characterizes HSC MTD. Central of this shift is a loss of expression of the master adipogenic regulator peroxisome proliferator activated receptor γ (PPARγ). Restored expression of PPARγ and/or other adipogenic transcription genes can reverse myofibroblastic HSCs to differentiated cells. Vertebrate Wnt and Drosophila wingless are homologous genes, and their translated proteins have been shown to participate in the regulation of cell proliferation, cell polarity, cell differentiation, and other biological roles. More recently, Wnt signaling is implicated in human fibrosing diseases, such as pulmonary fibrosis, renal fibrosis, and liver fibrosis. Blocking the canonical Wnt signal pathway with the co-receptor antagonist Dickkopf-1 (DKK1) abrogates these epigenetic repressions and restores the gene PPARγ expression and HSC differentiation. The identified morphogen mediated epigenetic regulation of PPARγ and HSC differentiation also serves as novel therapeutic targets for liver fibrosis and liver regeneration. In conclusion, the Wnt signaling promotes liver fibrosis by enhancing HSC activation and survival, and we herein discuss what we currently know and what we expect will come in this field in the next future.
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