Down-regulation of DNA Methyltransferase 1 by Peroxisome Proliferator-Activated Receptor Gamma in Hepatic Stellate Cells
Year: 2012
Type: dissertation
Abstract: DNA methyltransferase (DNMT) 1 is a critical enzyme which is mainly responsible for conversion of unmethylated DNA into hemimethylated DNA. Previous studies have suggested that enzymes related to DNA methylation play a very important role in liver fibrosis. In this study, we identified a significant over-expression of DNMT1 in activated hepatic stellate cells (HSCs), which suggests a vital function of DNMT1 in HSCs transactivation. Interestingly, ligand activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) in activated HSCs led to efficient down-regulation of DNMT1 expression. Furthermore, the PPAR-γ ligand rosiglitazone (RSG) dramatically down-regulated the expression of DNMT1 and up-regulated the expression of PPAR-γ during the transactivation of primary rat HSCs, suggesting an important role of PPAR-γ in HSC transactivation. Reporter assays showed that ligand activation of PPAR-γ inhibited transcriptional activation of the human DNMT1 gene promoter and such inhibition was rescued by transfection of nuclear factor-kappaB (NF-κB) expression vector pCMV-p50 and pCMV-p65, which indicates that PPAR-γ suppress DNMT1 expression via negatively interfering with NF-κB binding activity on DNMT1 promoter. Conclusion: These studies suggest that PPAR-γ may play a role in inhibiting HSCs transactivation by suppressing expression of DNMT1.
Author: Jilong Li
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W126085503