Comparative transcriptional network modeling of three PPAR-α/γ co-agonists reveals distinct metabolic gene signatures in primary human hepatocytes.
Comparative transcriptional network modeling of three PPAR-α/γ co-agonists reveals distinct metabolic gene signatures in primary human hepatocytes.
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DOI：
10.1371/journal.pone.0035012
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Edgar A
中科院分区：
文献类型：
--
作者：
Deehan R;Maerz-Weiss P;Catlett NL;Steiner G;Wong B;Wright MB;Blander G;Elliston KO;Ladd W;Bobadilla M;Mizrahi J;Haefliger C;Edgar A
比较平衡双重过氧化物酶体增殖物激活受体（PPAR）-α/γ激动剂阿格列扎与替格列扎（双重PPAR-α/γ激动剂）或吡格列酮（Pio; PPAR-γ激动剂）与非诺贝特（Feno; PPAR-α激动剂）联合用药在人肝细胞中的分子和生物学特征。基因表达微阵列图谱从用EC 50-对准的低、中和高浓度的三种处理剂处理的原代人肝细胞获得。一种系统生物学方法，因果网络建模，被用来模拟数据，以推断上游分子机制，可以解释所观察到的基因表达的变化。阿格列扎，tesaglitazar和Pio/Feno各自诱导独特的转录特征，尽管可比较的核心PPAR信号。尽管所有治疗均推断出定性相似的PPAR-α信号传导，但由于高密度和低密度脂蛋白代谢相关途径中更多的基因表达变化，推测阿格列扎对高密度和低密度脂蛋白胆固醇水平的影响大于替格列扎和Pio/Feno。不同的转录和生物签名也推断出应激反应，这似乎是受阿格列扎比对照。特别是，Pio/Feno被推断为增加NFE 2L 2活性，这是应激反应途径的关键组分，而阿格列扎没有显著影响。推断所有处理降低增殖信号传导。Aleglitazar诱导与脂质参数和应激反应相关的转录特征，这与其他双重PPAR-α/γ治疗不同。这可能是在阿格列扎的动物和临床研究中观察到的脂质特征有利变化的基础，并表明与其他双重PPAR-α/γ激动剂治疗相比存在差异化的基因特征。
To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist, aleglitazar, with tesaglitazar (a dual PPAR-α/γ agonist) or a combination of pioglitazone (Pio; PPAR-γ agonist) and fenofibrate (Feno; PPAR-α agonist) in human hepatocytes. Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC50-aligned low, medium and high concentrations of the three treatments. A systems biology approach, Causal Network Modeling, was used to model the data to infer upstream molecular mechanisms that may explain the observed changes in gene expression. Aleglitazar, tesaglitazar and Pio/Feno each induced unique transcriptional signatures, despite comparable core PPAR signaling. Although all treatments inferred qualitatively similar PPAR-α signaling, aleglitazar was inferred to have greater effects on high- and low-density lipoprotein cholesterol levels than tesaglitazar and Pio/Feno, due to a greater number of gene expression changes in pathways related to high-density and low-density lipoprotein metabolism. Distinct transcriptional and biologic signatures were also inferred for stress responses, which appeared to be less affected by aleglitazar than the comparators. In particular, Pio/Feno was inferred to increase NFE2L2 activity, a key component of the stress response pathway, while aleglitazar had no significant effect. All treatments were inferred to decrease proliferative signaling. Aleglitazar induces transcriptional signatures related to lipid parameters and stress responses that are unique from other dual PPAR-α/γ treatments. This may underlie observed favorable changes in lipid profiles in animal and clinical studies with aleglitazar and suggests a differentiated gene profile compared with other dual PPAR-α/γ agonist treatments.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.7
作者：
Bell, Ming;Wang, Hong;Chen, Hui;McLenithan, John C.;Gong, Da-Wei;Yang, Rong-Zee;Yu, Daozhan;Fried, Susan K.;Quon, Michael J.;Londos, Constantine;Sztalryd, Carole
通讯作者：
Sztalryd, Carole
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
6.5
作者：
Blander, Gil;Bhimavarapu, Anupama;Loureiro, Joseph Jorge
通讯作者：
Loureiro, Joseph Jorge
影响因子：
4
作者：
Delerive, P;Fruchart, JC;Staels, B
通讯作者：
Staels, B