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
More filters
Journal ArticleDOI
Brain-derived neurotrophic factor regulates cholesterol metabolism for synapse development.
Shingo Suzuki,Kazuyuki Kiyosue,Shunsuke Hazama,Shunsuke Hazama,Akihiko Ogura,Megumi Kashihara,Tomoko Hara,Hisatsugu Koshimizu,Masami Kojima +8 more
TL;DR: It is shown that BDNF elicits cholesterol biosynthesis in cultured cortical and hippocampal neurons, and this results suggest a novel role for BDNF in cholesterol metabolism and synapse development.
Journal ArticleDOI
Regulatory potential of n-3 fatty acids in immunological and inflammatory processes
TL;DR: N-3 fatty acids provide positive effects on various states of immune deficiencies and diseases with a hyperinflammatory character, among which selected examples are presented.
Journal ArticleDOI
7-Dehydrocholesterol–dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome
Barbara U. Fitzky,Fabian F. Moebius,Hitoshi Asaoka,Heather G. Waage-Baudet,Liwen Xu,Guorong Xu,Nobuyo Maeda,Kimberly D. Kluckman,Sylvia Hiller,Hongwei Yu,Ashok K. Batta,Sarah Shefer,Thomas S. Chen,Gerald Salen,Kathleen Sulik,Robert D. Simoni,Gene C. Ness,Hartmut Glossmann,Shailendra B. Patel,G.S. Tint +19 more
TL;DR: It is demonstrated that in mice without Dhcr7 activity, accumulated 7-dehydrocholesterol suppresses sterol biosynthesis posttranslationally, which might exacerbate abnormal development in SLOS by increasing the fetal cholesterol deficiency.
Journal ArticleDOI
SREBP-1 Interacts with Hepatocyte Nuclear Factor-4α and Interferes with PGC-1 Recruitment to Suppress Hepatic Gluconeogenic Genes
Takashi Yamamoto,Hitoshi Shimano,Yoshimi Nakagawa,Tomohiro Ide,Naoya Yahagi,Takashi Matsuzaka,Masanori Nakakuki,Akimitsu Takahashi,Hiroaki Suzuki,Hirohito Sone,Hideo Toyoshima,Ryuichiro Sato,Nobuhiro Yamada +12 more
TL;DR: The data indicate that SREBP-1 has a novel role as negative regulator of gluconeogenic genes through a cross-talk with HNF-4α interference with PGC-1 recruitment.
Journal ArticleDOI
Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements
Lauren M. Cagen,Xiong Deng,Henry G. Wilcox,Edwards A. Park,Rajendra Raghow,Rajendra Raghow,Marshall B. Elam,Marshall B. Elam +7 more
TL;DR: It is proposed that the combined actions of the SRE, LXREs, Sp1 and NF-Y elements constitute an insulin-responsive cis-acting unit of theSREBP-1c gene in the liver.
References
More filters
Journal ArticleDOI
A simple method for displaying the hydropathic character of a protein
Jack Kyte,Russell F. Doolittle +1 more
TL;DR: A computer program that progressively evaluates the hydrophilicity and hydrophobicity of a protein along its amino acid sequence has been devised and its simplicity and its graphic nature make it a very useful tool for the evaluation of protein structures.
Journal ArticleDOI
Functional rafts in cell membranes
Kai Simons,Elina Ikonen +1 more
TL;DR: A new aspect of cell membrane structure is presented, based on the dynamic clustering of sphingolipids and cholesterol to form rafts that move within the fluid bilayer that function as platforms for the attachment of proteins when membranes are moved around inside the cell and during signal transduction.
Journal ArticleDOI
The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor
TL;DR: This research was supported by grants from the National Institutes of Health (HL20948) and the Perot Family Foundation.
Journal ArticleDOI
The Caveolae Membrane System
TL;DR: Caveolae constitute an entire membrane system with multiple functions essential for the cell and are capable of importing molecules and delivering them to specific locations within the cell, exporting molecules to extracellular space, and compartmentalizing a variety of signaling activities.
Journal ArticleDOI
Molecular cloning and expression of brain-derived neurotrophic factor.
Joachim Leibrock,Friedrich Lottspeich,Hohn Andreas,Magdalena Hofer,Bastian Hengerer,Piotr Masiakowski,Hans Thoenen,Yves-Alain Barde +7 more
TL;DR: The full primary structure of brain-derived neurotrophic factor is reported and it is established that these two neurotrophic factors are related both functionally and structurally.