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A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood
Abstract
The integrity of cell membranes is maintained by a balance between the amount of cholesterol and the amounts of unsaturated and saturated fatty acids in phospholipids. This balance is maintained by membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) that activate genes encoding enzymes of cholesterol and fatty acid biosynthesis. To enhance transcription, the active NH 2 -terminal domains of SREBPs are released from endoplasmic reticulum membranes by two sequential cleavages. The first is catalyzed by Site-1 protease (S1P), a membrane-bound subtilisin-related serine protease that cleaves the hydrophilic loop of SREBP that projects into the endoplasmic reticulum lumen. The second cleavage, at Site-2, requires the action of S2P, a hydrophobic protein that appears to be a zinc metalloprotease. This cleavage is unusual because it occurs within a membrane-spanning domain of SREBP. Sterols block SREBP processing by inhibiting S1P. This response is mediated by SREBP cleavage-activating protein (SCAP), a regulatory protein that activates S1P and also serves as a sterol sensor, losing its activity when sterols overaccumulate in cells. These regulated proteolytic cleavage reactions are ultimately responsible for controlling the level of cholesterol in membranes, cells, and blood.
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Intracellular cholesterol levels play a primary role in determining hepatic LDLR expression levels through a negative feedback mechanism controlling gene transcription mediated by SRE in the LDLR promoter and SREBPs.
“many studies have demonstrated that intracellular cholesterol levels play a primary role in determination of hepatic LDLR expression levels through a negative feedback mechanism that controls gene transcription mediated by the sterol-regulatory element (SRE) located in LDLR promoter and SRE binding proteins (SREBPs)”
From A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression (2014) · cites this paper as [7]
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Simons, K., & Ikonen, E. (1997) · Nature · doi:10.1038/42408 · Cited by 9,757
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Metadata
- Authors
- Brown, M. S., & Goldstein, J. L.
- Affiliations
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-09-28
- Volume
- 96
- Issue
- 20
- Pages
- 11041-11048
- ISSN
- 0027-8424
- 1091-6490
- Cited by
- 1,134
- References
- 1
- Language
- en
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