DLK1/PREF1 regulates nutrient metabolism and protects from steatosis
DLK1/PREF1 regulates nutrient metabolism and protects from steatosis
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DOI：
10.1073/pnas.1406119111
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发表时间：
2014-11-11
影响因子：
11.1
通讯作者：
Ferguson-Smith, Anne C.
中科院分区：
文献类型：
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作者：
Charalambous, Marika;Da Rocha, Simao Teixeira;Ferguson-Smith, Anne C.
非酒精性脂肪性肝病(NAFLD)与胰岛素抵抗、肥胖以及进行性肝功能障碍有关。最近的动物研究强调了肝脏生长激素(GH)信号在NAFLD发生发展中的重要性。印迹Delta样同系物1(Dlk1)/前脂肪细胞因子1(Pref1)基因编码一种复杂的蛋白质，可产生循环和膜系留亚型，其表达剂量在功能上很重要，因为即使在胚胎发育过程中轻微的升高也会导致死亡。DLK1在胚胎发生、哺乳和怀孕期间在母亲体内表达上调。我们通过过量表达内源性控制元件的DLK1，研究了增加DLK1剂量的正常作用。增加DLK1的剂量可以改善糖耐量，即使在极端的代谢应激下，脂肪组织的扩张也不会出现原发性缺陷。相反，Dlk1的过度表达导致脂肪储存减少，垂体胰岛素样生长因子1(IGF1)抵抗，以及生长激素反馈调节的缺陷。循环性生长激素的增加最终导致全身燃料代谢的改变和肝脏脂肪变性的减少。我们认为，DLK1的功能是改变机体的代谢模式，使其转向外周脂肪氧化，而不是脂质储存，从而介导与早期生命相关的重要生理适应，并与代谢性疾病抗性有关。
Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance and obesity, as well as progressive liver dysfunction. Recent animal studies have underscored the importance of hepatic growth hormone (GH) signaling in the development of NAFLD. The imprinted Delta-like homolog 1 (Dlk1)/preadipocyte factor 1 (Pref1) gene encodes a complex protein producing both circulating and membrane-tethered isoforms whose expression dosage is functionally important because even modest elevation during embryogenesis causes lethality. DLK1 is up-regulated during embryogenesis, during suckling, and in the mother during pregnancy. We investigated the normal role for elevated DLK1 dosage by overexpressing Dlk1 from endogenous control elements. This increased DLK1 dosage caused improved glucose tolerance with no primary defect in adipose tissue expansion even under extreme metabolic stress. Rather, Dlk1 overexpression caused reduced fat stores, pituitary insulin-like growth factor 1 (IGF1) resistance, and a defect in feedback regulation of GH. Increased circulatory GH culminated in a switch in whole body fuel metabolism and a reduction in hepatic steatosis. We propose that the function of DLK1 is to shift the metabolic mode of the organism toward peripheral lipid oxidation and away from lipid storage, thus mediating important physiological adaptations associated with early life and with implications for metabolic disease resistance.