Sterol regulatory element-binding protein
Sterol regulatory element-binding transcription factor 1 | |||||||
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Chr. 17 p11.2 | |||||||
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sterol regulatory element-binding transcription factor 2 | |||||||
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Identifiers | |||||||
Symbol | SREBF2 | ||||||
Chr. 22 q13 | |||||||
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Sterol regulatory element-binding proteins (SREBPs) are
Isoforms
Mammalian genomes have two separate SREBP genes (SREBF1 and SREBF2):
- SREBP-1 expression produces two different isoforms, SREBP-1a and -1c. These isoforms differ in their first exons owing to the use of different transcriptional start sites for the SREBP-1 gene. SREBP-1c was also identified in rats as ADD-1. SREBP-1c is responsible for regulating the genes required for de novo lipogenesis.[6]
- SREBP-2 regulates the genes of cholesterol metabolism.[6]
Function
SREB proteins are indirectly required for
Mechanism of action
Animal cells maintain proper levels of intracellular
A notable feature of this regulatory feedback machinery was first observed for the SREBP pathway -
A feature of the SREBP pathway is the proteolytic release of a membrane-bound transcription factor, SREBP. Proteolytic cleavage frees it to move through the cytoplasm to the nucleus. Once in the nucleus, SREBP can bind to specific DNA sequences (the sterol regulatory elements or SREs) that are found in the control regions of the genes that encode enzymes needed to make lipids. This binding to
The ~120 kDa SREBP precursor protein is anchored in the membranes of the
In addition to S1P and S2P, the regulated release of transcriptionally active SREBP requires the cholesterol-sensing protein SREBP cleavage-activating protein (
Once in the Golgi apparatus, the SREBP-SCAP complex encounters active S1P. S1P cleaves SREBP at site-1, cutting it into two halves. Because each half still has a membrane-spanning helix, each remains bound in the membrane. The newly generated amino-terminal half of SREBP (which is the ‘business end' of the molecule) then goes on to be cleaved at site-2 that lies within its membrane-spanning helix. This is the work of S2P, an unusual metalloprotease. This releases the cytoplasmic portion of SREBP, which then travels to the nucleus where it activates transcription of target genes (e.g. LDL receptor gene)
Regulation
Absence of sterols activates SREBP, thereby increasing cholesterol synthesis.[11]
Insulin, cholesterol derivatives, T3 and other endogenous molecules have been demonstrated to regulate the SREBP1c expression, particularly in rodents. Serial deletion and mutation assays reveal that both SREBP (SRE) and LXR (LXRE) response elements are involved in SREBP-1c transcription regulation mediated by insulin and cholesterol derivatives. Peroxisome proliferation-activated receptor alpha (PPARα) agonists enhance the activity of the SREBP-1c promoter via a DR1 element at -453 in the human promoter. PPARα agonists act in cooperation with LXR or insulin to induce lipogenesis.[12]
A medium rich in branched-chain amino acids stimulates expression of the SREBP-1c gene via the
mTORC1 activation is not sufficient to stimulate hepatic SREBP-1c in the absence of Akt signaling, revealing the existence of an additional downstream pathway also required for this induction which is proposed to involve mTORC1-independent Akt-mediated suppression of INSIG-2a, a liver-specific transcript encoding the SREBP-1c inhibitor INSIG2.[14]
SREBP-1c has also been shown to upregulate in a tissue specific manner the expression of PGC1alpha expression in brown adipose tissue.[16]
History
The SREBPs were elucidated in the laboratory of Nobel laureates Michael Brown and Joseph Goldstein at the University of Texas Southwestern Medical Center in Dallas. Their first publication on this subject appeared in October 1993.[3][18]
References
External links
- Sterol+Regulatory+Element+Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- The Brown and Goldstein Lab Archived 2009-05-26 at the Wayback Machine.
- Cholesterol Synthesis Archived 2017-07-04 at the Wayback Machine - has some good regulatory details
- Protein Data Base (PDB), Sterol Regulatory Element Binding 1A structure.