title: Hedgehog controls hepatic stellate cell fate by regulating metabolism.
abstract: OBJECTIVE
  The pathogenesis of cirrhosis, a disabling outcome of defective liver repair, involves deregulated accumulation of myofibroblasts derived from quiescent hepatic stellate cells (HSCs), but the mechanisms that control transdifferentiation of HSCs are poorly understood. We investigated whether the Hedgehog (Hh) pathway controls the fate of HSCs by regulating metabolism.
  
  
  METHODS
  Microarray, quantitative polymerase chain reaction, and immunoblot analyses were used to identify metabolic genes that were differentially expressed in quiescent vs myofibroblast HSCs. Glycolysis and lactate production were disrupted in HSCs to determine if metabolism influenced transdifferentiation. Hh signaling and hypoxia-inducible factor 1α (HIF1α) activity were altered to identify factors that alter glycolytic activity. Changes in expression of genes that regulate glycolysis were quantified and localized in biopsy samples from patients with cirrhosis and liver samples from mice following administration of CCl(4) or bile duct ligation. Mice were given systemic inhibitors of Hh to determine if they affect glycolytic activity of the hepatic stroma; Hh signaling was also conditionally disrupted in myofibroblasts to determine the effects of glycolytic activity.
  
  
  RESULTS
  Transdifferentiation of cultured, quiescent HSCs into myofibroblasts induced glycolysis and caused lactate accumulation. Increased expression of genes that regulate glycolysis required Hh signaling and involved induction of HIF1α. Inhibitors of Hh signaling, HIF1α, glycolysis, or lactate accumulation converted myofibroblasts to quiescent HSCs. In diseased livers of animals and patients, numbers of glycolytic stromal cells were associated with the severity of fibrosis. Conditional disruption of Hh signaling in myofibroblasts reduced numbers of glycolytic myofibroblasts and liver fibrosis in mice; similar effects were observed following administration of pharmacologic inhibitors of Hh.
  
  
  CONCLUSIONS
  Hedgehog signaling controls the fate of HSCs by regulating metabolism. These findings might be applied to diagnosis and treatment of patients with cirrhosis.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; Section of Gastroenterology, Department of Medicine, Durham Veterans Affairs Medical Center, Durham, North Carolina.
authors.forename: Steve S
authors.initials: SS
authors.lastname: Choi
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Michelotti
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Chan
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Marzena
authors.initials: M
authors.lastname: Swiderska-Syn
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Gamze F
authors.initials: GF
authors.lastname: Karaca
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Xie
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; Section of Gastroenterology, Department of Medicine, Durham Veterans Affairs Medical Center, Durham, North Carolina.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Moylan
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Francesca
authors.initials: F
authors.lastname: Garibaldi
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Richard
authors.initials: R
authors.lastname: Premont
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: Hagir B
authors.initials: HB
authors.lastname: Suliman
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina; Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina; Department of Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina. Electronic address: diehl004@mc.duke.edu.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts; D002251:Carbon Tetrachloride; D054338:Cell Transdifferentiation / Q000235:genetics*; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019344:Lactic Acid / Q000378:metabolism; D008026:Ligation; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria; D058628:Myofibroblasts / Q000201:enzymology / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000235:genetics*; D013997:Time Factors
chemical_list: D000199:Actins; D053823:Hedgehog Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; C544013:alpha-smooth muscle actin, mouse; D019344:Lactic Acid; D002251:Carbon Tetrachloride; D011770:Pyruvate Kinase