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Regulation of cholesterol biosynthesis by SREBP (SREBF)
Stable Identifier
R-HSA-1655829
DOI
10.3180/REACT_147797.1
Type
Pathway
Species
Homo sapiens
Compartment
endoplasmic reticulum membrane
,
ER to Golgi transport vesicle membrane
,
Golgi membrane
,
nucleoplasm
ReviewStatus
5/5
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Metabolism (Homo sapiens)
Metabolism of lipids (Homo sapiens)
Metabolism of steroids (Homo sapiens)
Regulation of cholesterol biosynthesis by SREBP (SREBF) (Homo sapiens)
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Sterol regulatory element binding proteins (SREBPs, SREBFs) respond to low cholesterol concentrations by transiting to the nucleus and activating genes involved in cholesterol and lipid biosynthesis (reviewed in Brown and Goldstein 2009, Osborne and Espenshade 2009, Weber et al. 2004).
Newly synthesized SREBPs are transmembrane proteins that bind SCAP in the endoplasmic reticulum (ER) membrane. SCAP binds cholesterol which causes a conformational change that allows SCAP to interact with INSIG, retaining the SCAP:SREBP complex in the ER. INSIG binds oxysterols, which cause INSIG to bind SCAP and retain SCAP:SREBP in the endoplasmic reticulum.
In low cholesterol (below about 5 mol%) SCAP no longer interacts with cholesterol or INSIG and binds Sec24 of the CopII coat complex instead. Thus SCAP:SREBP transits with the CopII complex from the ER to the Golgi. In the Golgi SREBP is cleaved by S1P and then by S2P, releasing the N-terminal fragment of SREBP into the cytosol. The N-terminal fragment is imported to the nucleus by importin-beta and then acts with other factors, such as SP1 and NF-Y, to activate transcription of target genes. Targets of SREBP include the genes encoding all enzymes of cholesterol biosynthesis and several genes involved in lipogenesis. SREBP2 most strongly activates cholesterol biosynthesis while SREBP1C most strongly activates lipogenesis.
Literature References
PubMed ID
Title
Journal
Year
18974038
Cholesterol feedback: from Schoenheimer's bottle to Scap's MELADL
Brown, MS
,
Goldstein, JL
J Lipid Res
2009
19933148
Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been
Osborne, TF
,
Espenshade, PJ
Genes Dev
2009
15457548
Maintaining cholesterol homeostasis: sterol regulatory element-binding proteins
Stampfl, A
,
Boll, M
,
Weber, LW
World J Gastroenterol
2004
Participants
Events
SREBP1A,1C,2 binds SCAP:cholesterol:INSIG and is retained in the endoplasmic reticulum
(Homo sapiens)
SREBP1A,1C,2 binds SCAP:INSIG:oxysterol and is retained in the endoplasmic reticulum
(Homo sapiens)
SREBP1A,1C,2:SCAP binds CopII Coat Complex
(Homo sapiens)
SREBP1A,1C,2:SCAP translocates to the Golgi
(Homo sapiens)
S1P hydrolyzes SREBP1A,1C,2
(Homo sapiens)
S2P hydrolyzes SREBP1A,1C,2
(Homo sapiens)
SREBP1A,1C,2 binds SREBP1A,1C,2 forming dimers
(Homo sapiens)
SREBP1A,1C,2 binds Importin beta-1
(Homo sapiens)
SREBP1A,1C,2 translocates to the nucleus
(Homo sapiens)
SREBP1A,1C,2:Importin beta-1 dissociates
(Homo sapiens)
Activation of gene expression by SREBF (SREBP)
(Homo sapiens)
Participates
as an event of
Metabolism of steroids (Homo sapiens)
Event Information
Go Biological Process
regulation of cholesterol biosynthetic process (0045540)
Orthologous Events
Regulation of cholesterol biosynthesis by SREBP (SREBF) (Bos taurus)
Regulation of cholesterol biosynthesis by SREBP (SREBF) (Caenorhabditis elegans)
Regulation of cholesterol biosynthesis by SREBP (SREBF) (Canis familiaris)
Regulation of cholesterol biosynthesis by SREBP (SREBF) (Danio rerio)
Regulation of cholesterol biosynthesis by SREBP (SREBF) (Drosophila melanogaster)
Regulation of cholesterol biosynthesis by SREBP (SREBF) (Gallus gallus)
Regulation of cholesterol biosynthesis by SREBP (SREBF) (Mus musculus)
Regulation of cholesterol biosynthesis by SREBP (SREBF) (Rattus norvegicus)
Regulation of cholesterol biosynthesis by SREBP (SREBF) (Sus scrofa)
Regulation of cholesterol biosynthesis by SREBP (SREBF) (Xenopus tropicalis)
Authored
May, B (2011-09-28)
Reviewed
Liang, G (2012-08-26)
Created
May, B (2011-10-13)
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