title: Loss of Sept4 exacerbates liver fibrosis through the dysregulation of hepatic stellate cells.
abstract: OBJECTIVE
  Septins are ubiquitous and multifunctional scaffold proteins involved in cytoskeletal organization, exocytosis and other cellular processes. We disclose the quiescent hepatic stellate cells (HSCs)-specific expression of a septin subunit Sept4 in the liver, and explore the significance of the septin system in liver fibrosis.
  
  
  METHODS
  We analyzed the expression of alpha-smooth muscle actin (alpha-SMA), collagens and other markers in primary cultured HSCs derived from wild-type and Sept4(-/-) mice. We compared susceptibility of these mice to liver fibrosis induced by either carbon tetrachloride treatment, bile duct ligation or methionine/choline-deficient diet. Collagen deposition, the principal parameter of liver fibrosis, was quantified both histochemically (Masson's trichrome stain) and biochemically (hydroxyproline content).
  
  
  RESULTS
  In vitro, Sept4 mRNA/protein was remarkably downregulated in HSCs through myofibroblastic transformation. Sept4(-/-) HSCs showed normal morphology and proliferation, while myofibroblastic transformation as monitored by the upregulation of alpha-SMA and collagen was accelerated compared to wild-type HSCs. In vivo, liver fibrosis was consistently more severe in Sept4(-/-) mice than in wild-type littermates in all of the three paradigms of hepatitis/liver fibrosis.
  
  
  CONCLUSIONS
  These data concordantly indicate that the HSC-specific septin subunit Sept4 and perhaps the septin system are involved in the suppressive modulation of myofibroblastic transformation and fibrogenesis associated with liver diseases.
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwaisako
authors.forename: Etsuro
authors.initials: E
authors.lastname: Hatano
authors.forename: Kojiro
authors.initials: K
authors.lastname: Taura
authors.forename: Akio
authors.initials: A
authors.lastname: Nakajima
authors.forename: Masaharu
authors.initials: M
authors.lastname: Tada
authors.forename: Satoru
authors.initials: S
authors.lastname: Seo
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Tamaki
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Sato
authors.forename: Iwao
authors.initials: I
authors.lastname: Ikai
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D020558:GTP Phosphohydrolases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D055166:Hepatic Stellate Cells / Q000473:pathology / Q000502:physiology*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058112:Septins
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D012333:RNA, Messenger; D003094:Collagen; D020558:GTP Phosphohydrolases; C115474:Sept4 protein, mouse; D058112:Septins