Loss of Sept4 exacerbates liver fibrosis through the dysregulation of hepatic stellate cells.
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.
Iwaisako
Keiko
K
Department of Surgery, Graduate School of Medicine, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Hatano
Etsuro
E
Taura
Kojiro
K
Nakajima
Akio
A
Tada
Masaharu
M
Seo
Satoru
S
Tamaki
Nobuyuki
N
Sato
Fumiaki
F
Ikai
Iwao
I
Uemoto
Shinji
S
Kinoshita
Makoto
M
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
D000199:Actins; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D012333:RNA, Messenger; D003094:Collagen; D020558:GTP Phosphohydrolases; C115474:Sept4 protein, mouse; D058112:Septins