Frontiers in Pharmacology (May 2018)
DNA Methylation of PTGIS Enhances Hepatic Stellate Cells Activation and Liver Fibrogenesis
- Xue-yin Pan,
- Xue-yin Pan,
- Xue-yin Pan,
- Yang Yang,
- Yang Yang,
- Yang Yang,
- Hong-wu Meng,
- Hong-wu Meng,
- Hong-wu Meng,
- Hai-di Li,
- Hai-di Li,
- Hai-di Li,
- Xin Chen,
- Xin Chen,
- Xin Chen,
- Hui-min Huang,
- Hui-min Huang,
- Hui-min Huang,
- Fang-tian Bu,
- Fang-tian Bu,
- Fang-tian Bu,
- Hai-xia Yu,
- Hai-xia Yu,
- Hai-xia Yu,
- Qin Wang,
- Qin Wang,
- Qin Wang,
- Cheng Huang,
- Cheng Huang,
- Cheng Huang,
- Xiao-ming Meng,
- Xiao-ming Meng,
- Xiao-ming Meng,
- Jun Li,
- Jun Li,
- Jun Li
Affiliations
- Xue-yin Pan
- The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Xue-yin Pan
- The Key Laboratory of Anti-inflammatory of Immune Medicine, Ministry of Education, Hefei, China
- Xue-yin Pan
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
- Yang Yang
- The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Yang Yang
- The Key Laboratory of Anti-inflammatory of Immune Medicine, Ministry of Education, Hefei, China
- Yang Yang
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
- Hong-wu Meng
- The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Hong-wu Meng
- The Key Laboratory of Anti-inflammatory of Immune Medicine, Ministry of Education, Hefei, China
- Hong-wu Meng
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
- Hai-di Li
- The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Hai-di Li
- The Key Laboratory of Anti-inflammatory of Immune Medicine, Ministry of Education, Hefei, China
- Hai-di Li
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
- Xin Chen
- The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Xin Chen
- The Key Laboratory of Anti-inflammatory of Immune Medicine, Ministry of Education, Hefei, China
- Xin Chen
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
- Hui-min Huang
- The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Hui-min Huang
- The Key Laboratory of Anti-inflammatory of Immune Medicine, Ministry of Education, Hefei, China
- Hui-min Huang
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
- Fang-tian Bu
- The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Fang-tian Bu
- The Key Laboratory of Anti-inflammatory of Immune Medicine, Ministry of Education, Hefei, China
- Fang-tian Bu
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
- Hai-xia Yu
- The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Hai-xia Yu
- The Key Laboratory of Anti-inflammatory of Immune Medicine, Ministry of Education, Hefei, China
- Hai-xia Yu
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
- Qin Wang
- The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Qin Wang
- The Key Laboratory of Anti-inflammatory of Immune Medicine, Ministry of Education, Hefei, China
- Qin Wang
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
- Cheng Huang
- The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Cheng Huang
- The Key Laboratory of Anti-inflammatory of Immune Medicine, Ministry of Education, Hefei, China
- Cheng Huang
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
- Xiao-ming Meng
- The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Xiao-ming Meng
- The Key Laboratory of Anti-inflammatory of Immune Medicine, Ministry of Education, Hefei, China
- Xiao-ming Meng
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
- Jun Li
- The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China
- Jun Li
- The Key Laboratory of Anti-inflammatory of Immune Medicine, Ministry of Education, Hefei, China
- Jun Li
- Institute for Liver Diseases of Anhui Medical University, Hefei, China
- DOI
- https://doi.org/10.3389/fphar.2018.00553
- Journal volume & issue
-
Vol. 9
Abstract
The activation of hepatic stellate cells (HSCs) is a central event in the progression of liver fibrosis. Multiple studies proved that DNA methylation might accelerate HSCs activation. However, the specific pathogenesis of liver fibrosis remains not fully addressed. Our laboratory performed Genome methylation screening to find out the methylated gene in mice with liver fibrosis. The pilot experiments showed that the promoter of prostacyclin synthase (PTGIS) gene was hypermethylated in CCl4-induced liver fibrosis mouse model. Moreover, the down-regulated PTGIS expression can be restored by DNMTs-RNAi and 5-aza-2-deoxycytidine (5-azadC), an inhibitor of DNA methyltransferase (DNMTs). Methylation-specific PCR (MSP) showed that the methylation status of PTGIS in HSC-T6 cells cultures with TGF-β1 (10 ng/mL) was elevated compared with control group. Chromatin immunoprecipitation (ChIP) assay indicated that PTGIS methylation was mainly induced by DNMT1 and DNMT3b. We further investigated the function of PTGIS in liver fibrosis by Recombinant Hepatic-adeno-associated virus (rAAV8)-PTGIS overexpression. The data indicated that overexpression of PTGIS in mouse liver accompanied by elevated apoptosis-related proteins expression in primary HSCs. Conversely, PTGIS silencing mediated by RNAi enhanced the expression of α-SMA and COL1a1 in vitro. Those results illustrated that adding PTGIS expression inhibits the activation of HSCs and alleviates liver fibrosis. Therefore, our study unveils the role of PTGIS in HSCs activation, which may provide a possible explanation for CCl4-mediated liver fibrosis.
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