Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor
Yan Lu, E Wang, Ying Chen, Bing Zhou, Jiejie Zhao, Liping Xiang, Yiling Qian, Jingjing Jiang, Lin Zhao, Xuelian Xiong, Zhiqiang Lu, Duojiao Wu, Bin Liu, Jing Yan, Rong Zhang, Huijie Zhang, Cheng Hu, Xiaoying Li
Yan Lu, E Wang, Ying Chen, Bing Zhou, Jiejie Zhao, Liping Xiang, Yiling Qian, Jingjing Jiang, Lin Zhao, Xuelian Xiong, Zhiqiang Lu, Duojiao Wu, Bin Liu, Jing Yan, Rong Zhang, Huijie Zhang, Cheng Hu, Xiaoying Li
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Research Article Endocrinology Metabolism

Obesity-induced excess of 17-hydroxyprogesterone promotes hyperglycemia through activation of glucocorticoid receptor

Abstract

Type 2 diabetes mellitus (T2DM) has become an expanding global public health problem. Although the glucocorticoid receptor (GR) is an important regulator of glucose metabolism, the relationship between circulating glucocorticoids (GCs) and the features of T2DM remains controversial. Here, we show that 17-hydroxyprogesterone (17-OHP), an intermediate steroid in the biosynthetic pathway that converts cholesterol to cortisol, binds to and stimulates the transcriptional activity of GR. Hepatic 17-OHP concentrations are increased in diabetic mice and patients due to aberrantly increased expression of Cyp17A1. Systemic administration of 17-OHP or overexpression of Cyp17A1 in the livers of lean mice promoted the pathogenesis of hyperglycemia and insulin resistance, whereas knockdown of Cyp17A1 abrogated metabolic disorders in obese mice. Therefore, our results identify a Cyp17A1/17-OHP/GR–dependent pathway in the liver that mediates obesity-induced hyperglycemia, suggesting that selectively targeting hepatic Cyp17A1 may provide a therapeutic avenue for treating T2DM.

Authors

Yan Lu, E Wang, Ying Chen, Bing Zhou, Jiejie Zhao, Liping Xiang, Yiling Qian, Jingjing Jiang, Lin Zhao, Xuelian Xiong, Zhiqiang Lu, Duojiao Wu, Bin Liu, Jing Yan, Rong Zhang, Huijie Zhang, Cheng Hu, Xiaoying Li

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Figure 1

17-OHP induces GR transcriptional activity.

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17-OHP induces GR transcriptional activity. (A) Activation of GR by incr...
(A) Activation of GR by increasing doses of steroid hormone intermediates. HepG2 cells were transfected with a GRE-luciferase reporter and GR expression plasmid. Cells were deprived of FBS for 12 hours and treated with steroid hormone precursors for another 24 hours. Vehicle, ethanol; Dex (+, 10 nM; ++, 100 nM); 17-OHP (+, 0.1 μM; ++, 1 μM); other intermediates (+, 0.1 μM; ++, 1 μM). (B) Luciferase assays for GRE activity in HepG2 cells treated with or without 17-OHP (0.1 μM) for 24 hours. Cells were transfected with a GRE-luciferase reporter and intact GR or 2 truncated GR expression plasmids, as indicated. The first and second columns represent WT GR expression plasmid. The third and fourth columns represent LBD-Del GR expression plasmid. The fifth and sixth columns represent DBD-Del GR expression plasmid. LBD-Del, ligand binding domain–deleted GR; DBD-Del, DNA binding domain–deleted GR. (C) No activation of the ARE-, ERE-, FXRE-, and LXRE-luciferase reporters using different doses of 17-OHP in HepG2 cells. Cells were transfected with various luciferase reporters and the corresponding nuclear receptor expression plasmids. (D) Activation of the PEPCK promoter luciferase reporter in HepG2 cells treated with different doses of 17-OHP for 24 hours. Cells were cotransfected with PEPCK promoter reporters and GR expression plasmids. (E) Relative mRNA levels of PEPCK and TAT in MPHs treated with 17-OHP or vehicle control for 16 hours. (F) Relative mRNA levels of PEPCK and TAT in MPHs treated with 17-OHP (1μM) or 17-OHP plus RU486 (10 μM). Cells were pretreated with RU486 for 2 hours and then incubated with 17-OHP for another 16 hours. (G) Subcellular distribution of endogenous GR in MPHs treated with 17-OHP (0.1 μM) or vehicle control for 1 hour. (H) ChIP assays showing the recruitment of the GR onto the promoter region of the PEPCK and TAT genes. MPHs were treated with 17-OHP (0.1 μM) or vehicle control for 1 hour and then subjected to ChIP assays. (I) Coactivator recruitment dose-response curves for 17-OHP and Dex using a LanthaScreen GR coactivator assay kit. Data are represented as mean ± SD. **P < 0.01, and ***P < 0.001, 1-way ANOVA followed by the Student-Newman-Keuls test (A, C, D, E, F, and H) or 2-tailed unpaired Student’s t test (B).