Downregulation of the Wnt antagonist Dkk2 links loss of Sept4 and myofibroblastic transformation of hepatic stellate cells

ABSTRACT: Background/Aims: Sept4, a subunit of the septin cytoskeleton specifically expressed in quiescent hepatic stellate cells (HSCs), is downregulated through transdifferentiation to fibrogenic and contractile myofibroblastic cells. Since Sept4−/− mice are prone to liver fibrosis, we examined the unknown molecular network underlying liver fibrosis by probing the association between loss of Sept4 and accelerated transdifferentiation of HSCs. Methods: We compared the transcriptomes of Sept4+/+ and Sept4−/− HSCs by differential DNA microarray analysis and quantitative RT-PCR. Based on reduced dickkopf2 (Dkk2) gene expression in Sept4−/− HSCs, we tested whether supplementing Dkk2 could suppress myofibroblastic transformation of Sept4−/− HSCs. We used a lymphoid enhancer-binding factor/transcription factor-luciferase reporter assay to test whether Dkk2 can exert anti-fibrotic effects by interfering with the canonical Wnt pathway. Results: We observed consistent upregulation of Dkk2 in primary cultured HSCs and in a carbon tetrachloride hepatitis model in mice, which decreased with loss of Sept4. Supplementing Dkk2 suppressed the induction of pro-fibrotic genes (α-smooth muscle actin and 2 collagen genes) and induced an anti-fibrotic gene (Smad7) in Sept4−/− HSCs. In human liver specimens with inflammation and fibrosis, Dkk2 immunoreactivity appeared to be positively correlated with the degree of fibrotic changes. Conclusions: Pro-fibrotic transformation of HSCs through the loss of Sept4 is partly due to reduced expression of Dkk2 and its homologues, and the resulting disinhibition of the canonical Wnt pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE24588 | GEO | 2012/06/03

SECONDARY ACCESSION(S): PRJNA132373

REPOSITORIES: GEO