A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood
TLDR
These regulated proteolytic cleavage reactions are ultimately responsible for controlling the level of cholesterol in 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 NH2-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.read more
Citations
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Phosphorylation and ubiquitination of the transcription factor sterol regulatory element-binding protein-1 in response to DNA binding.
TL;DR: DNA binding could provide a mechanistic link between the phosphorylation, ubiquitination, and degradation of active transcription factors and is demonstrated to enhance the direct interaction between the C-terminal domain of SREBP1 and GSK-3β.
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pH regulation in Aspergillus and parallels with higher eukaryotic regulatory systems
TL;DR: This work focuses on the pH regulatory system of Aspergillus nidulans, where a novel signal transduction (pal) pathway mediates the first of two steps in the proteolytic processing of a transcription factor (PacC) that is reminiscent of that of some well-known higher eukaryotic transcription factors.
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Proteomic Analysis of Cleavage Events Reveals a Dynamic Two-step Mechanism for Proteolysis of a Key Parasite Adhesive Complex
TL;DR: The data support a novel two-step proteolysis model that includes primary processing of the MIC2/M2AP complex followed by secondary cleavage to shed the complex from the parasite surface during the final steps of invasion.
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Secreted proprotein convertase subtilisin/kexin type 9 reduces both hepatic and extrahepatic low-density lipoprotein receptors in vivo.
Robert J. Schmidt,Thomas P. Beyer,William R. Bensch,Yue-Wei Qian,Aiming Lin,Mark C. Kowala,William E. Alborn,Robert J. Konrad,Guoqing Cao +8 more
TL;DR: Evidence is presented that recombinant PCSK9, either injected intravenously into or expressed in the liver of C57BL/6 mice, significantly reduced LDLR levels in multiple extrahepatic tissues and indicates that secretedPCSK9 can potentially impact extrahePatic tissue cholesterol homeostasis by regulating extrahebatic tissue LDLR Levels.
Journal ArticleDOI
Diosgenin, the Main Aglycon of Fenugreek, Inhibits LXRα Activity in HepG2 Cells and Decreases Plasma and Hepatic Triglycerides in Obese Diabetic Mice
Taku Uemura,Tsuyoshi Goto,Min‑Sook Kang,Noriko Mizoguchi,Shizuka Hirai,Joo‑Yong Lee,Yuki Nakano,Jinji Shono,Shohei Hoshino,Keiko Taketani,Nobuaki Tsuge,Toshihiko Narukami,Makoto Makishima,Nobuyuki Takahashi,Teruo Kawada +14 more
TL;DR: It is suggested that fenugreek ameliorates dyslipidemia by decreasing the hepatic lipid content in diabetic mice and that its effect is mediated by diosgenin.
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