title: The forkhead transcription factor FoxO1 regulates proliferation and transdifferentiation of hepatic stellate cells.
abstract: OBJECTIVE
  The Forkhead box gene, group O (FoxO) family of Forkhead transcription factors is phopsphorylated and inactivated by the phosphatidylinositol 3-kinase (PI3K)/AKT pathway and regulates a variety of cellular functions. Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis. A fibrotic stimulus causes HSCs to transdifferentiate from a quiescent phenotype to a collagen-producing myofibroblast-like phenotype and to proliferate.
  
  
  METHODS
  Mutation/deletion mutants of FoxO1 were introduced into primary rat, mouse, and immortalized human HSCs and assessed for activation, proliferation, and signal transduction. The role of FoxO1 in experimental liver fibrosis was assessed in FoxO1(+/-) and FoxO1(+/+) mice.
  
  
  RESULTS
  Platelet-derived growth factor (PDGF) or insulin phosphorylates FoxO1 and induces FoxO1 translocation from the nuclei to the cytosol via the PI3K/AKT pathway in HSCs. Constitutively active FoxO1 inhibits proliferation via cell cycle arrest at the G1 phase, whereas dominant-negative FoxO1 enhances proliferation of HSCs even in the presence of the PI3K inhibitor LY294002. In addition, the phosphorylation of FoxO1 is increased during transdifferentiation of HSCs. The transdifferentiation is also inhibited by constitutively active FoxO1 and is accelerated by dominant-negative FoxO1. FoxO1 directly induces the expression of p27(kip1) and manganese superoxide dismutase (MnSOD). After bile duct ligation for 3 weeks, FoxO1(+/-) mice are more susceptible to liver fibrosis, consistent with our in vitro results.
  
  
  CONCLUSIONS
  FoxO1 plays a crucial role in the transdifferentiation and proliferation of HSCs in liver fibrosis. Hyperinsulinemia inactivates FoxO1 in HSCs, resulting in HSC activation and may result in the fibrosis in nonalcoholic fatty liver disease.
authors.affiliation: Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Adachi
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Osawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchinami
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Kitamura
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008106:Liver Cirrhosis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D012313:RNA / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: D002867:Chromones; D058534:Class I Phosphatidylinositol 3-Kinases; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007004:Hypoglycemic Agents; D007328:Insulin; D009025:Morpholines; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D012313:RNA; D013482:Superoxide Dismutase; C493961:Cdkn1b protein, mouse; C467200:Foxo1 protein, mouse; C075278:platelet-derived growth factor A; C074639:Foxo1 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C421683:Pik3cd protein, mouse