Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress
Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress
复制标题
DOI：
10.3177/jnsv.61.154
复制
发表时间：
2015-04-01
影响因子：
1.6
通讯作者：
Sato, Ryuichiro
中科院分区：
文献类型：
--
作者：
Shimizu, Makoto;Morimoto, Hitomi;Sato, Ryuichiro
成纤维细胞生长因子19（FGF 19）和FGF 21是称为内分泌FGF的FGFs亚家族的成员。FOP 19调节胆汁酸合成途径。FGF 19表达由法尼醇X受体（FXR）诱导，FXR是小肠中由胆汁酸激活的核激素受体。FGF 21在白色脂肪组织中发生的脂解中起重要作用。FGF 21的表达受到肝脏中核脂肪酸受体过氧化物酶体增殖物激活受体α（PPAR α）的刺激。FGF 19和FGF 21最近被鉴定为激活转录因子4（ATF 4）的靶点，所述激活转录因子4响应于内质网（ER）应激而被激活。ATF 4也被氧化应激和氨基酸剥夺激活。在这项研究中，我们研究了FGF 19和FGF 21的表达在氧化应激和氨基酸剥夺的反应。我们发现，FGF 19 mRNA的诱导氧化应激诱导剂在Caco-2细胞，这是来自人类肠上皮细胞，和大鼠肠上皮IEC 6细胞。相比之下，人FOP 19的啮齿动物直系同源物愈合FGF 15表达不因氧化应激而增加。无论在体外还是在体内，在氨基酸剥夺的情况下，FGF 15/19的表达没有显著的变化。相反，FGF 21的表达在体外和体内都是由氧化应激和氨基酸剥夺诱导的。这些结果表明，通过ER应激调节FGF 19表达的独特模式，以及通过ER应激、氧化应激和通过ATF 4活化的氨基酸剥夺调节FGF 21表达的独特模式。
Fibroblast growth factor 19 (FGF19) and FGF21 are members of a subfamily of the FGFs called endocrine FGFs. FOP 19 regulates the bile acid synthetic pathway. FGF19 expression is induced by farnesoid X receptor (FXR), a nuclear hormone receptor activated by bile acids in the small intestine. FGF21 plays an important role in lipolysis that occurs in white adipose tissue. FGF21 expression is stimulated by the nuclear fatty acid receptor peroxisome proliferator-activated receptor alpha (PPAR alpha) in the liver. FGF19 and FGF21 were recently identified as targets of activating transcription factor 4 (ATF4), which is activated in response to endoplasmic reticulum (ER) stress. ATF4 is also activated by oxidative stress and amino acid deprivation. In this study, we investigated FGF19 and FGF21 expression in response to oxidathie stress and amino acid deprivation. We found that FGF19 mRNA is induced by oxidative stress inducers in Caco-2 cells, which are derived from the human intestinal epithelium, and rat intestinal epithelial IEC6 cells. In contrast, heal FGF15 expression, the rodent ortholog of human FOP 19, is not increased by oxidative stress. No notable changes in expression of FGF15/19 took place under amino acid deprivation either in vitro or in vivo. In contrast, FGF21 expression is induced by oxidative stress and amino acid deprivation both in vitro and in vivo. These results indicate distinctive patterns of regulation of FGF19 expression by ER stress, and FGF21 expression by ER stress, oxidative stress, and amino acid deprivation through ATF4 activation.