M3: Cholesterol L22 Flashcards
Hyper-chylomicronemia can be caused by…
A) Lipoprotein Lipase deficiency B) ApoC-III mutations C) Apo E deficiency D) ABCA1 mutations E) apoA-I deficiency F) A, B, C G) D, E H) A, B, C, D, E
F) A, B, C
Abnormally high [LDL] in plasma can be caused by loss of function of…
A) LDL-R B) ApoB-100 C) ABCA1 D) Lipoprotein Lipase E) A, B F) C, D G) A, B, C, D
E) A, B
Low HDL concentrations may result from mutations in…
A) LDL-R B) Lipoprotein Lipase C) LCAT D) ABCA1 E) apoA-I F) A, B G) C, D, E H) A, B, C, D, E
G) C, D, E
What would occur in an LDLR deficiency?
If you have too much LDL (ex: LDL-R deficiency), then LDL will accumulate in the plasma and you will be at a high risk of developing cardiovascular disease.
What would occur in an ABCA-1 deficiency?
If you have a deficiency in ABCA-1 (tangier disease) you will have too little HDL, but the uptake of LDL is still functioning. So you will not have efflux of excess cholesterol and cholesterol will accumulate. You will then be at high risk of cardiovascular disease.
How can atherosclerosis occur in terms of LDL and HDL.
The accumulation of LDL will enter your intima media in your arteries, deposit there, and macrophages will be recruited there to clear out the debris. The macrophages will try to engulf the LDL, but they will become overwhelmed if they can’t efflux their cholesterol to HDL. So they undergo apoptosis and accumulate in a necrotic core. This recruits even more macrophages to digest the dead macrophages. Makes it even worse. So, you end up with cholesterol crystals in your arteries. This causes atherosclerosis (narrowing of arteries) which can cause a heart attack or stroke depending on which blood vessel is affected.
Look at lecture 22 Slides 14 - 20 for the synthesis of mevalonate and cholesterol.
lecture 22 Slides 14 - 20
How much energy is required to synthesize one cholesterol? Why is this significant?
36 ATP/Cholesterol
16 NADPH/Cholesterol
This is significant because cholesterol will not be degraded. It will be converted to other things because a lot of energy was used to make it.
How can cholesterol homeostasis be regulated at the level of the body?
Regulation at the level of the body: you can control the amount of cholesterol you intake. This is a way to modulate the amount of cholesterol that gets into your body.
If we ingest 300mg/day of cholesterol, we synthesize 700mg/day of cholesterol in the liver. So, our liver synthesizes more cholesterol than the uptake on a daily basis. So how do we keep a balance between the input and output? You have to excrete 1000mg/day of biliary cholesterol (bile salts derived from cholesterol).
So… you can control your diet but it is rly hard to control the amount of cholesterol being synthesized in the liver. \
How can cholesterol homeostasis be regulated at the level of the cell?
Regulation at the level of the cell: there is a way of controlling the amount of cholesterol at the surface of each cell. Remember, if you mess with the ratios of RAFTS and NON-RAFTS then your signalling will be screwed up.
- Regulate uptake of LDL through the regulation of LDLR. If you decrease the uptake, you decrease the intracellular concentration.
- If you can boost the efflux via ABCA1 you could also decrease the amount of cholesterol in the cell.
- Controlling the regulation of the endogenous production of cholesterol: this is done by controlling the regulatory enzyme HMG-CoA reductase (rate limiting step of cholesterol synthesis).
How is HMG-CoA reductase regulated?
- Energy state of the cell through phosphorylation
2. Concentration of cholesterol in the cell through gene regulation
Describe how HMG-CoA reductase is regulated by the energy of the cell.
HMG-CoA reductase can be fine tuned by the amount of energy in the cell. You need 36 ATP to synthesize cholesterol, therefore you will synthesize cholesterol when you’re in the high energy state. So if you have a high ratio of AMP to ATP your AMP activates AMP kinase which phosphorylates HMG-CoA reductase enzyme and makes it less active. Synthesis of cholesterol is abolished. When the ratio goes back to high levels of ATP, you wont activate AMPK, and protein phosphatase(PP1) will dephosphorylate HMG-CoA reductase and cholesterol will be synthesized.
Describe how HMG-CoA reductase is regulated by the concentration of cholesterol in the cell.
Low cholesterol: SREBP sits in the ER membrane and interacts with protein “Scap” which has a cholesterol sensing domain. When Scap is not interacting with cholesterol, it will take this whole complex ( SREBP + Scap), travel via vesicular transport all the way to the Golgi, and then in the Golgi the S1P (Site one protease) will cleave the SREBP tp generate a molecule that has a transcription factor (bHLH). This becomes a substrate for S2P (site 2 protease) which cleaves the bHLH part of SREBP to release the transcription factor. bHLH goes all the way to the nucleus, binds the Sterol responsive element, and activates transcription of HMG-CoA reductase gene (increase cholesterol synthesis) and LDL-R gene (increase cholesterol (LDL) uptake).
High cholesterol: Scap is interacting with cholesterol so the complex does not travel to the golgi. Nothing gets translocated to the nucleus, gene transcription is not affected.
How can cholesterol synthesis be pharmacologically regulated? A) HMG-CoA synthase inhibitors B) HMG-CoA synthase activators C) HMG-CoA reductase inhibitors D) HMG-CoA reductase activators
C) HMG-CoA reductase inhibitors
How do statins work?
They are pharmacological inhibitors of HMG-CoA reductase so that cholesterol is not synthesized.
Statins also decrease the concentrations of LDL.
