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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Animals, Biomarkers, Blotting, Western, Carbon Tetrachloride, Cells, Cultured, Gene Expression Profiling, Hepatic Stellate Cells, Hepatitis, Humans, Immunoenzyme Techniques, Immunoprecipitation, Inflammation, Intercellular Signaling Peptides and Proteins, Liver Cirrhosis, Luciferases, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myofibroblasts, Oligonucleotide Array Sequence Analysis, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Septins, Signal Transduction, Wnt Proteins.
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Does downregulation of the Wnt antagonist Dkk2 link the loss of Sept4 and myofibroblastic transformation of hepatic stellate cells? Context: 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 aimed to identify the unknown molecular network underlying liver fibrosis by probing the association between loss of Sept4 and accelerated transdifferentiation of HSCs. We compared the transcriptomes of Sept4(+/+) and Sept4(-/-) HSCs undergoing transdifferentiation by DNA microarray and quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis. Because Dickkopf2 (Dkk2) gene expression is reduced in Sept4(-/-) HSCs, we tested whether supplementing Dkk2 could suppress myofibroblastic transformation of Sept4(-/-) HSCs. We tested the involvement of the canonical Wnt pathway in this process by using a lymphoid enhancer-binding factor/transcription factor-luciferase reporter assay. We observed consistent upregulation of Dkk2 in primary cultured HSCs and in a carbon tetrachloride liver fibrosis in mice, which was decreased in the absence of Sept4. Supplementation with 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.
assistant
Pro-fibrotic transformation of HSCs through the loss of Sept4 is, in part, due to reduced expression of Dkk2 and its homologues, and the resulting disinhibition of the canonical Wnt pathway. Final Decision: yes