Related Experiment Video
Updated: Mar 10, 2026
11:27
Analysis of SCAP N-glycosylation and Trafficking in Human Cells
Published on: November 8, 2016
9.4K
The compound LY295427 antagonizes 25-hydroxycholesterol through binding to INSIG.
Xing-Yan Wen1, De-Jie Zhang2, Li-Ming He2
1State Key Laboratory of Metabolism and Regulation in Complex Organisms, College of Life Sciences, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
Journal of Lipid Research
|March 9, 2026
Summary
LY295427 prevents cholesterol metabolism disruption by 25-hydroxycholesterol (25-HC). This compound blocks 25-HC effects on sterol regulatory element-binding protein (SREBP) processing and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) degradation by targeting INSIG-1.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- 25-hydroxycholesterol (25-HC) regulates cholesterol homeostasis by inhibiting sterol regulatory element-binding protein (SREBP) maturation and promoting 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) degradation.
- The mechanism by which LY295427 reverses 25-HC-induced suppression of SREBP processing and its effect on HMGCR degradation remain unclear.
Purpose of the Study:
- To elucidate the mechanism of LY295427 in reversing 25-HC effects on cholesterol metabolism.
- To investigate whether LY295427 antagonizes the sterol-regulated degradation of HMGCR.
Main Methods:
- Investigated the interaction between SCAP and INSIG-1 in the presence of 25-HC and LY295427.
- Utilized a photoreactive LY295427-probe to identify direct binding targets.
- Assessed the effect of LY295427 on 25-HC-induced ubiquitination and degradation of HMGCR.
Main Results:
- LY295427 prevented the 25-HC-induced interaction between SCAP and INSIG-1, promoting SCAP translocation to the Golgi.
- Direct binding of LY295427 to INSIG-1 was demonstrated, with 25-HC competing for this binding.
- LY295427 inhibited 25-HC-induced ubiquitination and degradation of HMGCR.
Conclusions:
- LY295427 competes with 25-HC for binding to INSIG-1.
- This competition blunts 25-HC-induced inhibition of SREBP processing and HMGCR degradation, offering a novel therapeutic target for cholesterol metabolism disorders.
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