Paradoxical regulation of human FGF21 by both fasting and feeding signals: is FGF21 a nutritional adaptation factor?
Paradoxical regulation of human FGF21 by both fasting and feeding signals: is FGF21 a nutritional adaptation factor?
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DOI：
10.1371/journal.pone.0022976
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Takeda E
中科院分区：
文献类型：
--
作者：
Uebanso T;Taketani Y;Yamamoto H;Amo K;Ominami H;Arai H;Takei Y;Masuda M;Tanimura A;Harada N;Yamanaka-Okumura H;Takeda E
成纤维细胞生长因子21（Fibroblast growth factor 21，FGF 21）是近年来发现的一种参与调节小鼠糖脂代谢的代谢激素，但其在人体内的调节机制和作用尚不清楚。在这里，我们已经调查了人FGF 21基因在转录水平上的调控机制。对人FGF 21启动子（−1672至+230 bp）的缺失研究揭示了两种禁食信号，包括过氧化物酶体增殖物激活受体α（PPARα）和胰高血糖素信号，它们在小鼠原代肝细胞中独立诱导人FGF 21基因转录。此外，两种进食信号，葡萄糖和木糖醇，也剂量依赖性地诱导人FGF 21基因转录和mRNA表达在人HepG 2细胞和小鼠原代肝细胞。FGF 21蛋白表达和分泌也由高糖刺激诱导。人类FGF 21启动子（−1672至+230 bp）在−380至−366 bp处有一个碳水化合物反应元件，这与PPAR反应元件（PPRE）不同。通过RNAi敲低碳水化合物反应元件结合蛋白减少葡萄糖诱导的人FGF 21转录。此外，我们发现人FGF 21启动子区域的-555至-443 bp区域在基础转录的激活中发挥重要作用。总之，人FGF 21基因表达受到禁食和进食信号的矛盾且独立的调节。这些调节机制表明，人FGF 21随着营养危机而增加，包括饥饿和过度喂养。
Fibroblast growth factor 21 (FGF21) has recently emerged as a metabolic hormone involved in regulating glucose and lipid metabolism in mouse, but the regulatory mechanisms and actions of FGF21 in humans remain unclear. Here we have investigated the regulatory mechanisms of the human FGF21 gene at the transcriptional level. A deletion study of the human FGF21 promoter (−1672 to +230 bp) revealed two fasting signals, including peroxisome proliferator-activated receptor α (PPARα) and glucagon signals, that independently induced human FGF21 gene transcription in mouse primary hepatocytes. In addition, two feeding signals, glucose and xylitol, also dose-dependently induced human FGF21 gene transcription and mRNA expression in both human HepG2 cells and mouse primary hepatocytes. FGF21 protein expression and secretion were also induced by high glucose stimulation. The human FGF21 promoter (−1672 to +230 bp) was found to have a carbohydrate-responsive element at −380 to −366 bp, which is distinct from the PPAR response element (PPRE). Knock-down of the carbohydrate response element binding protein by RNAi diminished glucose-induced human FGF21 transcription. Moreover, we found that a region from −555 to −443 bp of the human FGF21 promoter region exerts an important role in the activation of basic transcription. In conclusion, human FGF21 gene expression is paradoxically and independently regulated by both fasting and feeding signals. These regulatory mechanisms suggest that human FGF21 is increased with nutritional crisis, including starvation and overfeeding.
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DOI：
10.1016/j.bbrc.2007.06.068
发表时间：
2007-08-24
影响因子：
3.1
作者：
Lundasen, Thomas;Hunt, Mary C.;Rudling, Mats
通讯作者：
Rudling, Mats
影响因子：
4.8
作者：
SHIH, HM;LIU, ZR;TOWLE, HC
通讯作者：
TOWLE, HC
影响因子：
7.7
作者：
Xu J;Lloyd DJ;Hale C;Stanislaus S;Chen M;Sivits G;Vonderfecht S;Hecht R;Li YS;Lindberg RA;Chen JL;Jung DY;Zhang Z;Ko HJ;Kim JK;Véniant MM
通讯作者：
Véniant MM
影响因子：
29
作者：
Badman, Michael K.;Pissios, Pavlos;Maratos-Flier, Eleftheria
通讯作者：
Maratos-Flier, Eleftheria
影响因子：
5.8
作者：
Dostalova, Ivana;Kavalkova, Petra;Haluzik, Martin
通讯作者：
Haluzik, Martin