DNA methylation patterns of peroxisome proliferator-activated receptor gamma gene associated with liver fibrosis and inflammation in chronic hepatitis B
DNA methylation patterns of peroxisome proliferator-activated receptor gamma gene associated with liver fibrosis and inflammation in chronic hepatitis B
复制标题
过氧化物酶体增殖物激活受体γ基因DNA甲基化模式与慢性乙型肝炎肝纤维化和炎症相关
DOI：
10.1111/jvh.12048
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发表时间：
2013-06-01
影响因子：
2.5
通讯作者：
Wang, K.
中科院分区：
文献类型：
--
作者：
Zhao, Q.;Fan, Y. -C.;Wang, K.
过氧化物酶体增殖物激活受体γ（PPAR γ）是一种核受体，在肝损伤中调节炎症介质的基因表达。B型肝炎病毒（HBV）抑制肝癌细胞系中过氧化物酶体增殖物激活受体γ介导的反式激活。然而，PPAR γ在慢性HBV感染患者中的作用尚未完全证实。本研究首先探讨慢性B型肝炎（CH B）患者外周血中过氧化物酶体增殖物激活受体γ（PPARgamma）mRNA水平的临床意义，然后研究PPARgamma启动子区DNA甲基化情况。从91名CHB患者和18名健康对照中分离外周血单个核细胞（PBMC）。实时荧光定量PCR检测细胞中PPAR γ mRNA水平，甲基化特异性PCR检测CpG岛甲基化。慢性乙型肝炎患者的PPAR γ mRNA水平显著低于健康对照组（P=0.005）。HBV-DNA阳性组mRNA水平较HBV-DNA阴性组降低（P=0.041）。相互作用分析表明，DNA甲基化模式是负责抑制外周PPAR γ转录在CHB患者（P=0.003）。此外，PPAR-gamma基因启动子的高甲基化与慢性乙型肝炎的肝脏炎症和纤维化显著相关。总之，DNA甲基化模式是CHB患者外周血PPAR γ mRNA水平下降的原因。肝脏炎症和纤维化与PPAR γ基因启动子甲基化有关。
Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor that regulates gene expression of inflammatory mediators in liver injury. Hepatitis B virus (HBV) suppresses the PPAR gamma-mediated transactivation in liver cancerous cell lines. However, the role of PPAR gamma in patients with chronic HBV infection has not fully demonstrated. Our present study was firstly to determine the clinical relevance of peripheral PPAR gamma mRNA levels in chronic hepatitis B (CHB) patients, and then, the DNA methylation of PPAR gamma promoter was investigated. Peripheral blood mononuclear cells (PBMCs) were isolated from 91 CHB patients and 18 healthy controls. The mRNA level of PPAR gamma was determined by quantitative real-time PCR; meanwhile, the CpG island methylation was assessed by methylation-specific PCR. CHB patients showed significantly lower mRNA level of PPAR gamma than healthy controls (P=0.005). The mRNA level was decreased in HBV-DNA-positive group than HBV-DNA-negative group (P=0.041). Interaction analysis demonstrated that the DNA methylation pattern was responsible for the suppression of peripheral PPAR gamma transcription in CHB patients (P=0.003). Furthermore, the hypermethylation of PPAR gamma gene promoter was significantly associated with liver inflammation and fibrosis in CHB. In conclusion, DNA methylation patterns were responsible for the decreased mRNA level of peripheral PPAR gamma in CHB patients. Liver inflammation and fibrosis were found to be associated with hypermethylation of PPAR gamma promoter.