Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome.
Chemical and Hormonal Effects on STAT5b-Dependent Sexual Dimorphism of the Liver Transcriptome.
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DOI：
10.1371/journal.pone.0150284
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Corton JC
中科院分区：
文献类型：
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作者：
Oshida K;Waxman DJ;Corton JC
生长激素（GH）激活的转录因子信号转导子和转录激活子5 b（STAT 5 b）是肝脏中性二态基因表达的关键调节因子。肝脏STAT 5 b信号传导的抑制与导致脂肪变性和肝癌的脂质代谢功能障碍相关。在配套出版物中，确定了一个STAT 5 b生物标志物基因集，并用于基于秩的检验，以高准确度（≥ 97%）预测肝脏STAT 5 b激活状态/功能的增加和减少。在这里，这种计算方法被用来确定化学品和激素，激活（男性化）或抑制（女性化）STAT 5 b功能在一个大的，注释的小鼠肝脏和原代肝细胞基因表达纲要。暴露于双氢睾酮和甲状腺激素导致肝脏男性化，而糖皮质激素，成纤维细胞生长因子15，血管紧张素II导致肝脏女性化。在糖尿病和肥胖症的小鼠模型中，始终观察到肝脏女性化，并且瘦素或白藜芦醇暴露至少部分逆转。化学诱导的雄性小鼠肝脏基因表达谱女性化是一种相对常见的现象：在化学处理的雄性小鼠的156个基因表达生物群中，29%显示肝脏STAT 5 b功能女性化，而<1%显示男性化。大多数（93%）表现出雄性肝脏雌性化的生物群也与一种或多种外源性反应受体的激活有关，最常见的是组成型激活受体（CAR）或过氧化物酶体增殖物激活受体α（PPARα）。女性化始终与过氧化物酶体增殖物激活受体γ（Pparg）的表达增加相关，但与脂肪变性相关的其他脂肪生成转录因子无关。因此，小鼠肝脏中GH激活的STAT 5 b信号传导通常会被不同的化学物质改变，并在化学物质暴露和与肝脏不良反应相关的基因表达失调之间提供了联系。
The growth hormone (GH)-activated transcription factor signal transducer and activator of transcription 5b (STAT5b) is a key regulator of sexually dimorphic gene expression in the liver. Suppression of hepatic STAT5b signaling is associated with lipid metabolic dysfunction leading to steatosis and liver cancer. In the companion publication, a STAT5b biomarker gene set was identified and used in a rank-based test to predict both increases and decreases in liver STAT5b activation status/function with high (≥ 97%) accuracy. Here, this computational approach was used to identify chemicals and hormones that activate (masculinize) or suppress (feminize) STAT5b function in a large, annotated mouse liver and primary hepatocyte gene expression compendium. Exposure to dihydrotestosterone and thyroid hormone caused liver masculinization, whereas glucocorticoids, fibroblast growth factor 15, and angiotensin II caused liver feminization. In mouse models of diabetes and obesity, liver feminization was consistently observed and was at least partially reversed by leptin or resveratrol exposure. Chemical-induced feminization of male mouse liver gene expression profiles was a relatively frequent phenomenon: of 156 gene expression biosets from chemically-treated male mice, 29% showed feminization of liver STAT5b function, while <1% showed masculinization. Most (93%) of the biosets that exhibited feminization of male liver were also associated with activation of one or more xenobiotic-responsive receptors, most commonly constitutive activated receptor (CAR) or peroxisome proliferator-activated receptor alpha (PPARα). Feminization was consistently associated with increased expression of peroxisome proliferator-activated receptor gamma (Pparg) but not other lipogenic transcription factors linked to steatosis. GH-activated STAT5b signaling in mouse liver is thus commonly altered by diverse chemicals, and provides a linkage between chemical exposure and dysregulated gene expression associated with adverse effects on the liver.