Loss of Sept4 exacerbates liver fibrosis through the dysregulation of hepatic stellate cells.

Abstract:

BACKGROUND/AIMS: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.

journal_name

J Hepatol

journal_title

Journal of hepatology

authors

Iwaisako K,Hatano E,Taura K,Nakajima A,Tada M,Seo S,Tamaki N,Sato F,Ikai I,Uemoto S,Kinoshita M

doi

10.1016/j.jhep.2008.05.026

subject

Has Abstract

pub_date

2008-11-01 00:00:00

pages

768-78

issue

5

eissn

0168-8278

issn

1600-0641

pii

S0168-8278(08)00360-7

journal_volume

49

pub_type

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