Epigenetic Regulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease: Impact of Liver Methylation of the Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Promoter
Epigenetic Regulation of Insulin Resistance in Nonalcoholic Fatty Liver Disease: Impact of Liver Methylation of the Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Promoter
复制标题
DOI：
10.1002/hep.23927
复制
发表时间：
2010-12-01
期刊：
影响因子：
13.5
通讯作者：
Pirola, Carlos J.
中科院分区：
文献类型：
--
作者：
Sookoian, Silvia;Soledad Rosselli, Maria;Pirola, Carlos J.
胰岛素抵抗（IR）和线粒体功能障碍在非酒精性脂肪性肝病（NAFLD）的病理生理学中起着核心作用。我们假设肝脏中发生的遗传因素和表观遗传修饰有助于IR表型。我们专门研究了脂肪肝和IR是否受到过氧化物酶体增殖物激活受体γ共激活因子1 α的肝脏DNA甲基化的修饰。（PPARGC 1A）和线粒体转录因子A（TEAM）启动子，并且还评估肝线粒体DNA（mtDNA）含量是否与NAFLD和IR相关。我们使用甲基化特异性聚合酶链反应（PCR）来评估PPARGC 1A和TFAM启动子中三个CpG的假定甲基化。时间PCR肝脏PPARGC 1A甲基化DNA/未甲基化DNA比率与血浆空腹胰岛素水平和胰岛素抵抗的稳态模型评估（HOMA-IR）相关，TFAM甲基化DNA/未甲基化DNA的比例与胰岛素水平呈负相关，PPARGC 1A启动子甲基化与肝脏PPARGC 1A信使RNA的丰度呈负相关。nDNA比值在对照组显著高于NAFLD组。mtDNA/nDNA比值与HOMA-IR、空腹血糖、胰岛素呈负相关，与PPARGC 1A启动子甲基化呈负相关。结论IR表型与PPARGC 1A的转录活性存在密切的相互作用，可能通过表观遗传修饰肝脏线粒体DNA含量降低同时导致外周IR（HEPATOLOGY 2010，52 1992-2000）
Insulin resistance (IR) and mitochondrial dysfunction play a central role in the pathophysiology of nonalcoholic fatty liver disease (NAFLD) We hypothesized that genetic factors and epigenetic modifications occurring in the liver contribute to the IR phenotype We specifically examined whether fatty liver and IR are modified by hepatic DNA methylation of the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) and mitochondrial transcription factor A (TEAM) promoters, and also evaluated whether liver mitochondrial DNA (mtDNA) content is associated with NAFLD and IR We studied liver biopsies obtained from NAFLD patients in a case control design After bisulfite treatment of DNA, we used methylation-specific polymerase chain reaction (PCR) to assess the putative methylation of three CpG in the PPARGC1A and TFAM promoters Liver mtDNA quantification using nuclear DNA (nDNA) as a reference was evaluated by way of real-time PCR Liver PPARGC1A methylated DNA/unmethylated DNA ratio correlated with plasma fasting insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR), TFAM methylated DNA/unmethylated DNA ratio was inversely correlated with insulin levels PPARGC1A promoter methylation was inversely correlated with the abundance of liver PPARGC1A messenger RNA The liver mtDNA/nDNA ratio was significantly higher in control livers compared with NAFLD livers mtDNA/nDNA ratio was inversely correlated with HOMA-IR, fasting glucose, and insulin and was inversely correlated with PPARGC1A promoter methylation Conclusion Our data suggest that the IR phenotype and the liver transcriptional activity of PPARGC1A show a tight interaction, probably through epigenetic modifications Decreased liver mtDNA content concomitantly contributes to peripheral IR (HEPATOLOGY 2010,52 1992-2000)