The Necdin-Wnt Pathway Causes Epigenetic Peroxisome Proliferator-activated Receptor γ Repression in Hepatic Stellate Cells

• Published in: The Journal of biological chemistry Vol. 285; no. 40; pp. 30463 - 30471
• Main Authors: Zhu, Nian-Ling, Wang, Jiaohong, Tsukamoto, Hidekazu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2010; American Society for Biochemistry and Molecular Biology
• Subjects: Adipocyte; Adipogenesis - drug effects; Adipogenesis - genetics; Animals; Cell Biology; Cell Differentiation; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - metabolism; Epigenesis, Genetic - drug effects; Epigenesis, Genetic - genetics; Epigenetics; Fibrinogenesis; Gene Silencing; H3K27-Dimethylation; Hepatic Stellate Cells - metabolism; Histones - genetics; Histones - metabolism; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Male; MeCP2; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Molecular Bases of Disease; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; PPAR; PPAR gamma - genetics; PPAR gamma - metabolism; PPAR-γ; Rats; Rats, Wistar; Regeneration - drug effects; Regeneration - genetics; Signal Transduction; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt10b; Adipocyte; H3K27-Dimethylation; MeCP2; PPAR; Epigenetics; Cell Differentiation; PPAR-γ; Fibrinogenesis; Wnt10b
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.156703

Hepatic stellate cells (HSCs), vitamin A-storing liver pericytes, undergo myofibroblastic trans-differentiation or “activation” to participate in liver wound healing. This cellular process involves loss of regulation by adipogenic transcription factors such as peroxisome proliferator-activated receptor γ (PPARγ). Necdin, a melanoma antigen family protein, promotes neuronal and myogenic differentiation while inhibiting adipogenesis. The present study demonstrates that necdin is selectively expressed in HSCs among different liver cell types and induced during their activation in vitro and in vivo. Silencing of necdin with adenovirally expressed shRNA, reverses activated HSCs to quiescent cells in a manner dependent on PPARγ and suppressed canonical Wnt signaling. Promoter analysis, site-directed mutagenesis, and chromatin immunoprecipitation demonstrate that Wnt10b, a canonical Wnt induced in activated HSCs, is a direct target of necdin. Necdin silencing abrogates three epigenetic signatures implicated in repression of PPARγ: increased MeCP2 (methyl CpG binding protein 2) and HP-1α co-repressor recruitments to Pparγ promoter and enhanced H3K27 dimethylation at the exon 5 locus, again in a manner dependent on suppressed canonical Wnt. These epigenetic effects are reproduced by antagonism of canonical Wnt signaling with Dikkopf-1. Our results demonstrate a novel necdin-Wnt pathway, which serves to mediate antiadipogenic HSC trans-differentiation via epigenetic repression of PPARγ.