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Down-regulation of DNA Methyltransferase 1 by Peroxisome Proliferator-Activated Receptor Gamma in Hepatic Stellate Cells

LI, JILONG (2012) Down-regulation of DNA Methyltransferase 1 by Peroxisome Proliferator-Activated Receptor Gamma in Hepatic Stellate Cells. Master's Thesis, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
LI, JILONGjil98@pitt.eduJIL98
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFolan, Maggiefolanm@pitt.eduFOLANM
Committee CoChairLi, Songsol4@pitt.eduSOL4
Committee MemberLi, Jiangjil35@pitt.eduJIL35
Date: 1 August 2012
Date Type: Publication
Defense Date: 26 July 2012
Approval Date: 1 August 2012
Submission Date: 1 August 2012
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 47
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Hepatic Stellate Cells (HSCs); DNA Methyltrasferase (DNMT) 1; Peroxisome proliferator-activated receptor gamma (PPAR-γ); nuclear factor-kappaB (NF-κB); gene regulation.
Date Deposited: 02 Aug 2012 00:07
Last Modified: 15 Nov 2016 14:00


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