Lipoproteins and receptors
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- What two organs are key in cholesterol balance?
- liver and the intestines
- What is added to a cholesterol during transport or storage?
- a fatty acid chain to the hydroxyl group
- What is the coat of lipoproteins principally made of?
- phospholipids (hydrophilic) and some apoproteins
- phospholipids are amphipathic, why does this suit the needs of the lipoproteins?
- it is stable with a aqueous environment and a non-polar core
- Besides being amphipathic, what other physical properties do they have that determine their function?
- So, besides stabilizing by being amphipathic, they have binding receptors and enzymes⬦ that help in attachment and activators respectively
- What special function do ApoA (A1)have?
- activate LCAT and receptor binding
- What special function do ApoB have?⬦ b) and what do their lipoproteins do? (B48, B100)
- a) receptor binding⬦b) 1. their lipoproteins deliver TAGs to muscle and fat tissue⬦ 2. they also remove cholesterol from the body " reverse cholesterol transport"
- What special function do ApoC have? (CII)
- Activates lipoprotein lipase (LPL)
- What special function do ApoE have? (E)
- Receptor binding
- What are the 3 steps in the life of a Apob lipoprotein?
- 1) assembly and secretion⬦ 2) intravascular metabolism⬦ 3) receptor mediated removal from blood plasma
- Where would you find the ApoB48 and ApoB100?
- ApoB48=intestines, Apo100=liver
- where is ApoB regulated? And how is it different in the liver versus the intestines and other tissues?
- ApoB mRNA editing⬦ b) liver transcribes entire gene and edits out only intron (B100=100%)⬦ the intestines premature stop codon (B48=48%)
- Which ApoB containing lipoprotein gives rise to LDL?
- ApoB100 = VLDL⬦ thus, it is the the B100 that is giving rise to atherosclerosis
- What role does MTP play in VLDL and CM?
- they introduce TAGs into the growing lipoprotein
- In what state is ApoB being produced?
- fed state⬦ otherwise it is degraded
- Do all Apo stay with a lipoprotein?
- no but ApoBs do⬦ others are exchangeable
- Which Apo must enter ApoB containing lipoproteins (CM) from HDLs? (exchange) Why?
- a) ApoCII⬦ b) it activates the lipoprotein, such that it allows binding to lipoprotein lipase (LPL), thus fatty acids are released from TAGs and enter the cell (muscle or fat)
- After the ApoB lipoprotein (CM) has unloaded its TAG, why does it swap its newly acquired ApoCII for a ApoE with an HDL? Biochemical reason and function
- a) having lost its TAGs, the ApoB lipoprotein is smaller and has more affinity for the ApoE⬦ b) the ApoE targets it for the liver to be recycled.
- What is the general cause for the formation of LDLs?
- they are the product of the less efficient clearance of VLDLs
- What liver cell surface protein does the CM's ApoE bind?
- LRP = (LDL receptor related protein)
- What is the half-life of the process of CM synthesis and breakdown?
- 1/2 hour
- How do 50% of the VLDL remnants get cleared from blood plasma?
- an LDL receptor on the liver uptakes the remnant for recycling
- What happens to the other 50% of VLDL remanants?
- some go back to the fat or muscle cell and unload more TAGs⬦ these are called IDLs
- What causes some of the VLDL remnants to become LDLs?
- The remnant binds to a liver surface receptor that is much like the ApoCr (found on Lipoprotein lipase near fat and muscle cells)⬦ it then unload the rest of its TAG and fatty acids and glycerol is taken up by the liver⬦ the remnant becomes more dense (but has a high percentage of cholesterol)... it loses it ApoE receptor due loss of affinity, thus it has not affinity for the LDL receptor
- What is the clearance half-life for VLDL remnants after it loses its ApoE receptor?
- 2.5 days
- What type of uptake does the LDL receptor mediate?
- receptor medicated endocytosis
- What happens to the cholesterol taken up by the the LDL?
- The VLDL remanant, after taken up by the LDL, goes to a lysosome, broken down, and the cholesterol is sent to the ER. The ER puts esters on the cholesterol and down regulates cholesterol synthesis.
- How does the cell down regulate cholesterol intake in the cell
- production of HMG co-enzyme reductase, which will down regulate the LDL receptors to avoid cholesterol overload (toxic)
- What is the problem with the long half-life of LDLs?
- They become oxidized, taken up by macrophages that can't stop taking up cholesterol⬦ they turn inot foam cells⬦ they can burst and then recruitment of more immune cells... and this leads to atherosclerosis
- What is the first step in HDL snthesis?
- ApoA1 is released by the liver… it immediately binds to the ABCA1 receptor, which then form a pre-ß-HDL (a little cholesterol and phospholipids)
- What converts the pre-ß-HDL into an HDL?
- the LCAT enzyme (it is actually an HDL-3 until it takes up cholesterol from cells.)
- What happens after the HDL is loaded with cholesterol?
- goes to the liver
- What is the liver receptor that takes up the HDL? And what is unique about it? What is an important plasma enzyme in this process?
- a) SRB1⬦ b) it allows the the injection of the cholesterol core and recycling of the ApoA1. Thus so every new ApoA1 is a LOT a little bit of old and a little bit of new⬦ c) LCAT
- How does LCAT work in making and HDL function?
- it takes a fatty acid off of a phospholipid and sticks it onto a cholesterol, making it a cholesterol-ester⬦ making more room for more another cholesterol⬦ this increases the HDL cholesterol capacity
- What does cholesterol-ester-tranfer-protein (CETP) do in HDL2 particles?
- It causes a swap of cholesterol for TAGs with ApoB particles⬦ the ApoB takes cholesterol back to the liver and the TAG helps the HDL2 function better. The HDL2 is free to retrieve more cholesterol
- What is the downside of CETP?
- some of the ApoB partilces become LDLs
- Which is the only organ that can break down cholesterol? What enzyme makes cholesterol degradation possible?
- a) the liver… b) cholesterol-7-∂-hydroxylase
- What is the role of micelles?
- a) Micelles transport cholesterol from the liver to the intestines through the biliary trail⬦ b) the help keep cholesterol and TAG in solution in the intestines
- How do micelles get pumped out of the liver cells?
- ATP pump called ABCD11, but overall similar to HDL formation
- How does cholesterol enter the enterocyte? How does regulation of cholesterol take place here?
- a) NPC1L1 channel⬦ b) some of the cholesterol get pumped back out
- Not all cholesterols are created equal. Since the liver goes through so much trouble making bile salts cholesterol, how is this product conserved? What is this process called?
- a) High affinity receptor in the ilium bring all the bile salts back⬦then back to the liver⬦ b) enterohepatic circulation
- What fraction of cholesterol do we synthesize?
- three times what we eat
- What do the current high cholesterol drugs do?
- They inhibit biosynthesis of cholesterol, lowever LDL cholesterol (by promoting LDL clearance.)
- What do cells make cholesterol from?
- acetate
- What do statins do to inhibit cholesterol synthesis?
- They inhibit HMG-CoA reductase
- How do drugs promote LDL clearance?
- up-regulate LDL receptors on the liver
- By what percentage do statins inhibit cholesterol synthesis? Is this enough?
- 40-50%⬦ yes
- What do bile salt sequestrants?
- Prevent reabsorption in the illium⬦ this will cause the use of cholesterol for more bile salts⬦. The liver then upregulates LDL receptors to replace cholesterol.
- What do cholesterol inhibitors do?
- Inhibit dietary cholesterol absorption⬦ and while the inhibit the biliary reabsorption, they really inhibit the formation of LDLs in the first place
- What do plant sterols to to inhibit cholesterol obsorption?
- competitive uptake inhibitor
- What does Ezetimibe do?
- they block cholesterol entrance into the intestinal cell
- What dodual inhibitors do?
- reduce cholesterol uptake and cholesterol synthesis⬦
- What does niacin do in lowering cholesterol?
- lowers LDLs by inhibiting VLDL production and raise the HDL level⬦ in the liver it decreases the renal clearance of ApoA1
- What do Fibrates do?
- decrease VLDL formation and balance the HDL (up or down) They also lower TAG⬦
- Why is this the drug of choice for the obese?
- They also lower TAGs