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 (?-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. We induced Liver Cirrhosis to SEPT4-KO or wild type mouse by CCl4, and examined mRNA expression profiling in hepatic stellate cell of these mouse.

ORGANISM(S): Mus musculus

SUBMITTER: Akira Myomoto 

PROVIDER: E-GEOD-24588 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress