The glucocorticoid receptor represses, whereas C/EBPβ can enhance or repress CYP26A1 transcription.
The glucocorticoid receptor represses, whereas C/EBPβ can enhance or repress CYP26A1 transcription.
复制标题
DOI：
10.1016/j.isci.2022.104564
复制
发表时间：
2022-07-15
期刊：
影响因子：
5.8
通讯作者：
Napoli JL
中科院分区：
文献类型：
--
作者：
Yoo HS;Rodriguez A;You D;Lee RA;Cockrum MA;Grimes JA;Wang JC;Kang S;Napoli JL
维甲酸（RA）对抗胰岛素的代谢作用。胰岛素通过将FoxO1从细胞核输出，减少肝脏中维甲酸的生物合成。维甲酸诱导其自身的分解代谢，这一过程由CYP26A1催化。此前尚未研究过CYP26A1在能量状态变化时对维甲酸体内平衡的作用。我们发现，胰高血糖素、皮质醇和地塞米松会降低维甲酸诱导的CYP26A1转录，从而在禁食期间减少维甲酸的氧化。糖皮质激素受体与RAR/RXR共激活复合物之间的相互作用会抑制CYP26A1的表达，延长维甲酸的消除半衰期。CCAAT增强子结合蛋白β（C/EBPβ）与单核苷酸多态性rs2068888的主要等位基因之间的相互作用会增强CYP26A1的表达；而次要等位基因则会限制C/EBPβ对CYP26A1的作用。主要等位基因和次要等位基因分别与人类健康受损或血液甘油三酯降低相关。因此，调节CYP26A1转录有助于调整维甲酸，使其协调能量供应与代谢。这些结果加深了我们对能量状态变化时CYP26A1对维甲酸的影响，以及糖皮质激素受体对RAR调控基因表达的修饰作用的理解。
**禁食期间糖皮质激素和胰高血糖素会增加肝脏维甲酸浓度**
- 糖皮质激素受体与RAR/RXR共激活复合物结合，降低CYP26A1转录
- C/EBPβ与单核苷酸多态性rs2068888的主要等位基因结合，增强CYP26A1转录
- C/EBPβ与单核苷酸多态性rs2068888的次要等位基因结合，抑制CYP26A1转录
**所属学科**：生物化学；生物科学；分子生物学
Retinoic acid (RA) counters insulin’s metabolic actions. Insulin reduces liver RA biosynthesis by exporting FoxO1 from nuclei. RA induces its catabolism, catalyzed by CYP26A1. A CYP26A1 contribution to RA homeostasis with changes in energy status had not been investigated. We found that glucagon, cortisol, and dexamethasone decrease RA-induced CYP26A1 transcription, thereby reducing RA oxidation during fasting. Interaction between the glucocorticoid receptor and the RAR/RXR coactivation complex suppresses CYP26A1 expression, increasing RA’s elimination half-life. Interaction between CCAAT-enhancer-binding protein beta (C/EBPβ) and the major allele of SNP rs2068888 enhances CYP26A1 expression; the minor allele restricts the C/EBPβ effect on CYP26A1. The major and minor alleles associate with impaired human health or reduction in blood triglycerides, respectively. Thus, regulating CYP26A1 transcription contributes to adapting RA to coordinate energy availability with metabolism. These results enhance insight into CYP26A1 effects on RA during changes in energy status and glucocorticoid receptor modification of RAR-regulated gene expression. Glucocorticoids and glucagon increase liver retinoic acid concentrations during fasting The glucocorticoid receptor binds to an RAR/RXR coactivation complex to reduce CYP26A1 transcription C/EBPβ binding to a major allele of SNP rs2068888 enhances CYP26A1 transcription C/EBPβ binding to a minor allele of SNP rs2068888 inhibits CYP26A1 transcription Biochemistry; Biological sciences; Molecular biology
登录
查看更多内容
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
10.5
作者：
Abu-Abed, S;Dollé, P;Petkovich, M
通讯作者：
Petkovich, M
影响因子：
64.8
作者：
HORLEIN, AJ;NAAR, AM;ROSENFELD, MG
通讯作者：
ROSENFELD, MG
影响因子：
5.3
作者：
Kane, Maureen A.;Folias, Alexandra E.;Napoli, Joseph L.
通讯作者：
Napoli, Joseph L.
影响因子：
64.8
作者：
CHEN, JD;EVANS, RM
通讯作者：
EVANS, RM