title: Hedgehog-mediated epithelial-to-mesenchymal transition and fibrogenic repair in nonalcoholic fatty liver disease.
abstract: OBJECTIVE
  Repair responses define the ultimate outcomes of liver disease. This study evaluated the hypothesis that fibrogenic repair in nonalcoholic fatty liver disease (NAFLD) is mediated by Hedgehog (Hh) pathway activation and consequent induction of epithelial-to-mesenchymal transitions (EMT) in ductular-type progenitors.
  
  
  METHODS
  Immature ductular cells were exposed to Sonic hedgehog (Shh) in the presence or absence of the Hh inhibitor cyclopamine to determine whether Hh-pathway activation directly modulates EMT in liver progenitors. Potential biologic correlates of progenitor cell EMT were assessed using mice fed methionine-choline-deficient + ethionine (MCDE) diets with or without cyclopamine. The effects of increased Hh signaling on EMT and fibrogenic repair during diet-induced NAFLD were also compared in wild-type (WT) and Patched haplo-insufficient (Ptc(+/-)) mice. Finally, evidence of Hh-pathway activation and EMT was examined in liver sections from patients with NAFLD.
  
  
  RESULTS
  In cultured progenitors, Shh repressed expression of epithelial genes and EMT inhibitors but induced genes that are expressed by myofibroblasts. Cyclopamine reversed these effects. In mouse NAFLD models, Hh-pathway activation, EMT, expansion of myofibroblastic populations, and liver fibrosis occurred. Cyclopamine inhibited Hh-pathway activation and induction of EMT. Ptc(+/-) mice, which have an overactive Hh pathway, exhibited sustained overinduction of Hh target genes and more EMT, myofibroblast accumulation, and fibrosis than WT mice. Numbers of Shh-producing cells and Hh-responsive ductular cells that expressed EMT markers increased in parallel with liver fibrosis in patients with NAFLD.
  
  
  CONCLUSIONS
  Hh-mediated EMT in ductular cells contributes to the pathogenesis of cirrhosis in NAFLD.
authors: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors: Wing-Kin
authors: WK
authors: Syn
authors: Youngmi
authors: Y
authors: Jung
authors: Alessia
authors: A
authors: Omenetti
authors: Manal
authors: M
authors: Abdelmalek
authors: Cynthia D
authors: CD
authors: Guy
authors: Liu
authors: L
authors: Yang
authors: Jiangbo
authors: J
authors: Wang
authors: Rafal P
authors: RP
authors: Witek
authors: Caitlin M
authors: CM
authors: Fearing
authors: Thiago A
authors: TA
authors: Pereira
authors: Vanessa
authors: V
authors: Teaberry
authors: Steve S
authors: SS
authors: Choi
authors: J
authors: J
authors: Conde-Vancells
authors: Gamze F
authors: GF
authors: Karaca
authors: Anna Mae
authors: AM
authors: Diehl
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D054338:Cell Transdifferentiation / Q000187:drug effects / Q000235:genetics; D002796:Choline Deficiency / Q000150:complications / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014704:Veratrum Alkaloids / Q000494:pharmacology
chemical_list: D053823:Hedgehog Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C509239:SHH protein, human; C465570:Shh protein, mouse; D014704:Veratrum Alkaloids; D008715:Methionine; C000541:cyclopamine