التفاصيل البيبلوغرافية
| العنوان: |
Proline hydroxylation of CREB-regulated transcriptional coactivator 2 controls hepatic glucose metabolism. |
| المؤلفون: |
Yaqian Xue, Aoyuan Cui, Shuang Wei, Fengguang Ma, Zhengshuai Liu, Xia Fang, Shaofeng Huo, Xiaoyang Sun, Wenjing Li, Zhimin Hu, Yuxiao Liu, Genxiang Cai, Weitong Su, Jiuxiang Zhao, Xi Yan, Chenlin Gao, Jian Wen, Haibing Zhang, Hong Li, Yi Liu |
| المصدر: |
Proceedings of the National Academy of Sciences of the United States of America; 6/6/2023, Vol. 120 Issue 23, p1-12, 37p |
| مصطلحات موضوعية: |
CREB protein, GLUCOSE metabolism, HYDROXYLATION, TYPE 2 diabetes, PROLINE |
| مستخلص: |
Prolyl hydroxylase domain (PHD) enzymes change HIF activity according to oxygen signal; whether it is regulated by other physiological conditions remains largely unknown. Here, we report that PHD3 is induced by fasting and regulates hepatic gluconeogenesis through interaction and hydroxylation of CRTC2. Pro129 and Pro615 hydroxylation of CRTC2 following PHD3 activation is necessary for its association with cAMP-response element binding protein (CREB) and nuclear translocation, and enhanced binding to promoters of gluconeogenic genes by fasting or forskolin. CRTC2 hydroxylation-stimulated gluconeogenic gene expression is independent of SIK-mediated phosphorylation of CRTC2. Liver-specific knockout of PHD3 (PHD3 LKO) or prolyl hydroxylase-deficient knockin mice (PHD3 KI) show attenuated fasting gluconeogenic genes, glycemia, and hepatic capacity to produce glucose during fasting or fed with high-fat, high-sucrose diet. Importantly, Pro615 hydroxylation of CRTC2 by PHD3 is increased in livers of fasted mice, diet-induced insulin resistance or genetically obese ob/ob mice, and humans with diabetes. These findings increase our understanding of molecular mechanisms linking protein hydroxylation to gluconeogenesis and may offer therapeutic potential for treating excessive gluconeogenesis, hyperglycemia, and type 2 diabetes. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
