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(Unpublished)
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.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| 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 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/13164 |
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