The mRNA-binding protein Zfp36 is upregulated by β-adrenergic stimulation and represses IL-6 production in 3T3-L1 adipocytes.
The mRNA-binding protein Zfp36 is upregulated by β-adrenergic stimulation and represses IL-6 production in 3T3-L1 adipocytes.
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DOI：
10.1038/oby.2011.259
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发表时间：
2012-01
期刊：
影响因子：
6.9
通讯作者：
Kallen, Caleb B.
中科院分区：
文献类型：
--
作者：
Brahma, Pavna K.;Zhang, Huanchun;Murray, Betsy S.;Shu, Feng-jue;Sidell, Neil;Seli, Emre;Kallen, Caleb B.
肥胖产生慢性炎症状态，导致糖尿病和动脉粥样硬化的发展。在肥胖人群中，脂肪库脂肪细胞和巨噬细胞产生炎症细胞因子和其他因素，产生不利的局部和全身免疫反应。许多细胞因子的表达在转录后水平受到mRNA结合蛋白的调控，这些蛋白识别这些转录物的3′-非翻译区（3′-UTR）中的富含AU的元件（战神）。已知一种这样的蛋白质，锌指蛋白36（Zfp 36），使靶mRNA不稳定，导致细胞因子表达降低。已经描述了脂肪细胞中Zfp 36表达的几种调节剂，并且脂肪细胞中Zfp 36的mRNA靶点在很大程度上是未知的。我们发现，巨噬细胞衍生的炎症刺激增强内源性Zfp 36在3 T3-L1脂肪细胞中的表达。此外，β-肾上腺素能受体激动剂异丙肾上腺素（Iso）和糖皮质激素地塞米松（Dex）各自增强脂肪细胞中Zfp 36的表达，前者最有可能通过环磷酸腺苷（cAMP）依赖性途径。相比之下，Zfp 36在小鼠巨噬细胞（RAW 264.7）的表达并没有增加暴露于地塞米松，但刺激视黄酸（RA）。Zfp 36抑制脂肪细胞中基础和脂多糖（LPS）刺激的白细胞介素-6（IL-6）表达。这些数据揭示了脂肪细胞和巨噬细胞中Zfp 36表达的重要和细胞类型特异性调节剂，并将Zfp 36鉴定为脂肪细胞衍生的IL-6的有效阻遏物。此外，这项工作确定了刺激脂肪细胞Zfp 36表达的新因子，这些因子既不是经典的炎症性因子，也不是促有丝分裂因子。上调mRNA结合蛋白用于治疗目的可以提供一种新的机制方法，用于治疗包括与肥胖相关的常见病症在内的多种炎性病症。
Obesity produces a chronic inflammatory state that contributes to the development of diabetes and atherosclerosis. In obese humans, fat depot adipocytes and macrophages produce inflammatory cytokines and other factors which exert unfavorable local and systemic immune responses. The expression of many cytokines is modulated at the post-transcriptional level by mRNA-binding proteins which recognize AU-rich elements (AREs) in the 3′-untranslated regions (3′-UTR) of these transcripts. One such protein, zinc finger protein 36 (Zfp36), is known to destabilize target mRNAs leading to decreased cytokine expression. Few regulators of Zfp36 expression in adipocytes have been described and mRNA targets of Zfp36 in adipocytes are largely unknown. We found that macrophage-derived inflammatory stimuli enhanced endogenous Zfp36 expression in 3T3-L1 adipocytes. Furthermore, the β-adrenergic receptor agonist isoproterenol (Iso) and the glucocorticoid dexamethasone (Dex) each enhanced Zfp36 expression in adipocytes, the former most likely via a cyclic adenosine monophosphate (cAMP)-dependent pathway. By contrast, Zfp36 expression in murine macrophages (RAW 264.7) was not enhanced by exposure to Dex but was stimulated by retinoic acid (RA). Zfp36 inhibited basal and lipopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) expression in adipocytes. These data reveal important and cell type-specific modulators of Zfp36 expression in adipocytes and macrophages and identify Zfp36 as a potent repressor of adipocyte-derived IL-6. Furthermore, this work identifies new factors that stimulate adipocyte Zfp36 expression that are neither classically inflammatory nor mitogenic. Upregulating an mRNA-binding protein for therapeutic purposes may provide a novel mechanistic approach with which to treat diverse inflammatory disorders including common conditions associated with obesity.
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影响因子：
5.8
作者：
Bouchard, Luigi;Vohl, Marie-Claude;Tchernof, Andre
通讯作者：
Tchernof, Andre
影响因子：
9.8
作者：
Fain, John N.;Buehrer, Ben;Madan, Atul K.
通讯作者：
Madan, Atul K.
肿瘤坏死因子-α的脂肪表达--在与肥胖相关的胰岛素抵抗中的直接作用
影响因子：
56.9
作者：
HOTAMISLIGIL, GS;SHARGILL, NS;SPIEGELMAN, BM
通讯作者：
SPIEGELMAN, BM
影响因子：
30.5
作者：
Han, Chaofeng;Jin, Jing;Cao, Xuetao
通讯作者：
Cao, Xuetao
影响因子：
6.9
作者：
Cao, Heping;Urban, Joseph F., Jr.;Anderson, Richard A.
通讯作者：
Anderson, Richard A.