Differentiated embryo chondrocyte 1 (DEC1) is a novel negative regulator of hepatic fibroblast growth factor 21 (FGF21) in aging mice
Differentiated embryo chondrocyte 1 (DEC1) is a novel negative regulator of hepatic fibroblast growth factor 21 (FGF21) in aging mice
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DOI：
10.1016/j.bbrc.2015.12.045
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发表时间：
2016-01-15
影响因子：
3.1
通讯作者：
Bhawal, Ujjal K.
中科院分区：
文献类型：
--
作者：
Fujita, Yu;Makishima, Makoto;Bhawal, Ujjal K.
人分化胚胎软骨细胞表达基因1（DEC1）常被用作体内衰老的标志物。成纤维细胞生长因子21（FGF21）是FGF超家族的一种新型内分泌样成员，在肝脏中高度表达，FGF21转基因小鼠的寿命延长。因此，我们假设FGF21可能在DEC 1介导的衰老过程中发挥作用。在这项研究中，DEC1基因敲除（KO）小鼠用于表征FGF 21保护小鼠免受衰老的机制。在DEC1 KO小鼠中，衰老明显减少，这反映在脂质水平降低和氧化应激，导致肝功能和结构改善。在野生型（WT）小鼠中，FGF21的表达随着年龄的增长而下降，而在DEC1 KO小鼠中，ATF4、磷酸化ERK和磷酸化p38的表达得以维持，并伴随着FGF21 mRNA和蛋白表达的代偿性升高。DEC1的过度表达显著地消除了肝脏中FGF21的表达，并且siRNA介导的内源性DEC1的抑制增加了FGF21的表达。DEC1进一步降低过表达DEC1的HepG2细胞中ATF4的表达。在衰老过程中在mRNA和蛋白水平上诱导FGF21和ATF 4支持DEC1 KO小鼠能够恢复与年龄相关的代谢失衡的观点。总的来说，在这项研究中获得的数据表明，DEC 1是一种新的负调节肝FGF21的表达。(C)2015 Elsevier Inc. All rights reserved.
Human differentiated embryo chondrocyte expressed gene 1 (DEC1) is frequently used as a marker of senescence in vivo. Fibroblast growth factor 21 (FGF21), a novel endocrine-like member of the FGF superfamily, is highly expressed in the liver, and FGF21-transgenic mice have extended lifespans. Thus, we hypothesized that FGF21 may play a role in the DEC1-mediated aging process. In this study, DEC1 knockout (KO) mice were used to characterize the mechanism by which FGF21 protects mice from aging. Aging is strongly diminished in DEC1 KO mice, which is reflected by decreased lipid levels and oxidative stress, leading to an amelioration of liver function and structure. The expression of FGF21 decreased with aging in wild-type (WT) mice, whereas ATF4, Phospho-ERK and Phospho-p38 expression was maintained and was accompanied by a compensatory rise of FGF21 mRNA and protein expression in DEC1 KO mice. Over-expression of DEC1 markedly abolished the hepatic expression of FGF21, and siRNA-mediated inhibition of endogenous DEC1 increased the expression of FGF21. DEC1 further diminished the expression of ATF4 in HepG2 cells over-expressing DEC1. The induction of FGF21 and ATF4 at the mRNA and protein levels during the course of aging supports the view that DEC1 KO mice are able to restore the age-related imbalance of metabolism. Collectively, the data obtained in this study suggest that DEC1 is a novel negative regulator of hepatic FGF21 expression. (C) 2015 Elsevier Inc. All rights reserved.