Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ
Joint Authors
Lu, X. P.
Wang, Wei
Liu, Nan-Song
Yang, Qian-Jiao
Zhang, Kun
Zhu, Jing-Zhong
Huang, Laiqiang
Li, Z. B.
Ning, Z. Q.
Shan, S.
Pan, D. S.
Source
Issue
Vol. 2017, Issue 2017 (31 Dec. 2017), pp.1-16, 16 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2017-09-19
Country of Publication
Egypt
No. of Pages
16
Main Subjects
Abstract EN
Type 2 diabetes mellitus is often treated with insulin-sensitizing drugs called thiazolidinediones (TZD), which improve insulin resistance and glycemic control.
Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent cardiovascular disease associated with diabetes.
Here we demonstrate how chiglitazar, a configuration-restricted non-TZD peroxisome proliferator-activated receptor (PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism.
CDK5-mediated phosphorylation at serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to insulin resistance in type 2 diabetes mellitus.
Our data demonstrates that chiglitazar modulates gene expression differently from two TZDs, rosiglitazone and pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ.
Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than rosiglitazone and pioglitazone in different cell models.
These increased expressions were dependent on the phosphorylation status of PPARγ at S273.
Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ.
Based on these results, activities from pan agonist chiglitazar can be an effective part of a long-term therapeutic strategy for treating type 2 diabetes in a more balanced action among its targeted organs.
American Psychological Association (APA)
Pan, D. S.& Wang, Wei& Liu, Nan-Song& Yang, Qian-Jiao& Zhang, Kun& Zhu, Jing-Zhong…[et al.]. 2017. Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ. PPAR Research،Vol. 2017, no. 2017, pp.1-16.
https://search.emarefa.net/detail/BIM-1197236
Modern Language Association (MLA)
Pan, D. S.…[et al.]. Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ. PPAR Research No. 2017 (2017), pp.1-16.
https://search.emarefa.net/detail/BIM-1197236
American Medical Association (AMA)
Pan, D. S.& Wang, Wei& Liu, Nan-Song& Yang, Qian-Jiao& Zhang, Kun& Zhu, Jing-Zhong…[et al.]. Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ. PPAR Research. 2017. Vol. 2017, no. 2017, pp.1-16.
https://search.emarefa.net/detail/BIM-1197236
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1197236