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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Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes.
Dalila Azzout-Marniche,Dominique Bécard,Colette Guichard,Marc Foretz,Pascal Ferré,Fabienne Foufelle +5 more
TL;DR: It is shown here in cultured rat hepatocytes that insulin, through activation of the phosphatidylinositol 3-kinase pathway increases the abundance of the precursor form of SREBP-1c in endoplasmic reticulum, leading to an increased content of the nuclear mature form of the transcription factor sterol regulatory-element-binding protein-1C.
Journal ArticleDOI
Polyunsaturated fatty acid regulation of gene transcription: a mechanism to improve energy balance and insulin resistance
TL;DR: The data discussed indicate that dietary PUFA function as fuel partitioners in that they direct glucose toward glycogen storage, and fatty acids away from triglyceride synthesis and assimilation and toward fatty acid oxidation, and the n-3 family of PUFA appear to have the unique ability to enhance thermogenesis and thereby reduce the efficiency of body fat deposition.
Journal ArticleDOI
Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling.
Tomohiro Yoshikawa,Tomohiro Ide,Hitoshi Shimano,Naoya Yahagi,Michiyo Amemiya-Kudo,Takashi Matsuzaka,Shigeru Yatoh,Tetsuya Kitamine,Hiroaki Okazaki,Yoshiaki Tamura,Motohiro Sekiya,Akimitsu Takahashi,Alyssa H. Hasty,Ryuichiro Sato,Hirohito Sone,Jun-ichi Osuga,Shun Ishibashi,Nobuhiro Yamada +17 more
TL;DR: PPARalpha activation can suppress LXR-SREBP-1c pathway through reduction of LXR/RXR formation, proposing a novel transcription factor cross-talk between LXR and PPARalpha in hepatic lipid homeostasis.
Journal ArticleDOI
Dual regulation of mouse Δ5- and Δ6-desaturase gene expression by SREBP-1 and PPARα
Takashi Matsuzaka,Hitoshi Shimano,Naoya Yahagi,Michiyo Amemiya-Kudo,Tomohiro Yoshikawa,Alyssa H. Hasty,Yoshiaki Tamura,Jun-ichi Osuga,Hiroaki Okazaki,Yoko Iizuka,Akimitsu Takahashi,Hirohito Sone,Takanari Gotoda,Shun Ishibashi,Nobuhiro Yamada +14 more
TL;DR: The data suggested that D5D and D6D expression is dually regulated by SREBP-1c and PPAR a , two reciprocal transcription factors for fatty acid metabolism, and could be involved in lipogenic gene regulation by producing PUFA.
Journal ArticleDOI
Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins.
TL;DR: It is shown that anti-MELADL blocks COPII binding in vitro, and microinjection of Fab anti-L blocks Scap·SREBP movement in cells, and it is speculated that sterols and Insig block SREBP transport by altering the location of MELadL with respect to the membrane, rendering it inaccessible to COPII proteins.
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TL;DR: This research was supported by grants from the National Institutes of Health (HL20948) and the Perot Family Foundation.
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