title: Wnt signaling in liver fibrosis: progress, challenges and potential directions.
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.
authors.affiliation: School of Pharmacy, Institute for Liver Diseases of Anhui Medical University, Anhui Key Laboratory of Bioactivity of Natural Products, Anhui Medical University, Mei Shan Road, Hefei 230032, Anhui Province, China; School of Food and Drug, Anhui Science and Technology University, Bengbu 233100, China.
authors.forename: Cheng-gui
authors.initials: CG
authors.lastname: Miao
authors.forename: Ying-ying
authors.initials: YY
authors.lastname: Yang
authors.forename: Xu
authors.initials: X
authors.lastname: He
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiong-Wen
authors.initials: XW
authors.lastname: Lv
authors.forename: Yong
authors.initials: Y
authors.lastname: Jin
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D054338:Cell Transdifferentiation / Q000502:physiology*; D055166:Hepatic Stellate Cells / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000503:physiopathology*; D008115:Liver Regeneration / Q000235:genetics; D047495:PPAR gamma / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D047495:PPAR gamma
keywords: 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