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

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 α-smooth muscle actin (α-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 α-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