Cholesterol 5 Flashcards
What is the link between the regulation of cholesterol and the regulation of fatty acid phospholipid metabolism?
They are controlled by the same mechanism
What are SREBP?
Sterol response element binding proteins
These are transcription factors that regulate cholesterol metabolism
What are the properties of SREBPs?
1150 amino acid membrane proteins in Endoplasmic reticulum
N-terminal is basic helix loop helix transcription factor (bHLH)
C terminal has the regulatory domain
How is the bHLH transcription factor released from SREBP
Release of the transcription factors requires proteolytic cleavage first by serine protease S1P in the luminal loop
(recognising Arg-Ser-Val-Leu-‘Ser)
Followed by cleavage at S2P in the trans membrane domain by a metalloprotease
What is SCAP?
SREBP Cleavage Activating Protein
It is an integral membrane protein of 1276 amino acids
8 Membrane spanning alpha-helical domains
5 of these have a cholesterol binding domain similar to that of HMG-coA reductase
C terminal has a WD motif which binds to the regulatory domain of SREBP
What is the cell biology problem faced by SREBP/SCAP cleavage and how is it solved?
SREBP and SCAP both have ER locations but the proteases needed for cleavage are in the golgi
This problem is solved by the fact that SCAP is a glycoprotein, these proteins get produced in the ER and then sent to golgi for modification
ER glycoproteins are sensitive to EndoH while golgi glycoproteins are resistant
As SCAP is resistant it must be sent to the ER
How is SCAP shuttled between the ER and the golgi?
If SCAP binds to SREBP it is retained in the ER, however cholesterol induces a conformational change in SCAP which causes the SREBP/SCAP complex to move to the golgi
This change is regulate by insig-1 as this prevents SREBP/SCAP transport to the golgi
Insig 1 will only bind to the complex in if cholesterol levels are adequate if the levels are insufficient it will release and the complex will move to the golgi to be cleaved
What is the role of the sterol sensing domain in HMG-coA reductase?
This domains senses high levels of cholesterol and its precursors
Its activation triggers rapid ubiquitin dependant proteasomal degradation of HMG-coA reductase
Reducing the amount of cholesterol produced
This involves cholesterol-dependent binding of Insig 1
How does AMPK regulate cholesterol synthesis?
AMPK acts as an intracellular sensor for energy levels
In the low energy state of high AMP levels and low ATP levels it will down regulate cholesterol synthesis through phosphorylation of HMG-coA reductase
Protein phosphatase can reactivate the protein by removing this phosphate
How is HMG-coA reductase regulated?
Via phosphorylation by AMP kinase
Statin drugs can mimic the substrate to competitively inhibit HMG-coA reductase
Regulated transcriptionally by SREBP/SCAP/Insig when cellular cholesterol levels are low
Regulated post transcriptionally by Insig-dependant and sterol-accelerated degradation
What is the point of having multiple SREB forms?
Allows differential supply of cholesterol or fatty acids or phospholipids
