LECTURE 20 - LIPOPROTEINS Flashcards
what is NPC1L1?
transporter for steroids on the intestine membrane
what does orlistat do?
lipase inhibitor
decreases the amount of chylomicrons in the blood
what does olestra do?
artificial fat, used as a food additive
non hydrolysable by lipases
it causes diarrhea caused by too many lipids in the digestive tract
what is the general structure of a lipoprotein?
polar surface envelope: phospholipids, cholesterol heads and apolipoproteins
hydrophobic core where you can store neutral lipids
neutral=hydrophobic
what are the functions of apolipoproteins?
serve as co factors for enzymes and/or docking factors for receptors
interact with the lipid core and coat the surface to hold it together
what are two amphiphilic molecules?
cholesterol and palmitoyl-oleoyl phosphatidylcholine
what are some two neutral molecules?
cholesteryl oleate and triacylglycerol
what is the definition of lipoproteins?
circulating lipid carriers composed of a neutral lipid core, a monolayer of polar surface lipids and at least one apolipoprotein
what is the definition of apolipoproteins and some main ones we should remember?
amphipatic proteins that insert in lipoproteins and serve as ligand for lipoprotein recognition and docking
ApoB-48 Apo B-100, Apo C, Apo E, Apo A-I
what is the increasing order of density of lipoproteins?
chylomicrons
VLDL
IDL
LDL
HDL
as the density increases the size decreases
what is the structure of chylomicrons?
part of the exogenous pathway, formed after a meal
lifespan is about 3 hours
has Apo E and Apo B-48, Apo CII and Apo CIII (the important ones)
which are the triaglyceride rich lipoproteins?
VLDL and chylomicrons
how does lipoprotein lipase (LPL) act on chylomicrons?
Apo C-II on the chylomicron activates LPL, which hydrolyses triglycerides into free fatty acids + monoacylglyceride
Apo C-III, also present on the chylomicron, acts as an inhibitor of LPL to maintain the equilibrium
the chylomicron is anchored to the LPL
this happens inside the capillary
the fatty acids + monoacylglyceride then go into the endothelial cells
delivers FFA to the muscle and adipose tissue
what happens to the chylomicrons after the capillaries?
what is left is called chylomicron remnants
does not have ApoC anymore, this remains attached to the LPL
the remnants then go to the liver, where they use ApoB-48 to dock to it?
what does the 48 in ApoB-48 mean?
48% of the length of the protein, it is made by the intestine
what is the structure of VLDL?
has Apo B-100 on the surface
Apo C and Apo E
the rest is standard lipoprotein structure
what does VLDL do?
part of the endogenous pathway, constitutively made
feeds the muscle and adipose tissue with leftovers from the liver
FFAs are used in muscle for energy and then in adipose tissue they are stored in case of starvation
what is left after that is the IDL
what is the structure of LDL?
ApoB-100
what does hepatic lipase do?
IDL+hepatic lipase -> LDL
removes the last triglycerides from the IDL
what does LDL do?
carries mostly cholesterol ester, triglycerides are taken care of by hepatic lipase
LDL only has Apo B
delivers cholesterol to peripheral tissues (anything but the liver), which use it for synthesis of steroid hormones
how does cholesterol uptake happen?
- Apo B-100 on the LDL is recognised by LDL receptors on the surface of the cell
- the LDL is taken up into a clathrin coated vesicle
- the clathrin leaves, you are left with the endosome, and the pH drops to around 5
- this releases the LDL receptors to be recycled back to the surface
- the endosome turns into a lysosome
- anything that is not cholesterol is ridden of and cholesterol ester goes to the endoplasmic reticulum
- the ER controls how much cholesterol is made
what is the structure of HDL?
mostly has Apo-A-I on surface
what is the main function of HDL?
prevent accumulation of lipids in tissues
where does HDL originate from?
originates from the peripheral tissues
what is the first stage of HDL transport?
liver produces ApoA-1 in unlipidated form
ApoA-1 interacts with ABCA1
what is ABCA1 and what does it do?
- ABCA1 (a floppase) is the rate lilimiting step for the synthesis of nascent HDL particles
- effluxes membrane lipids onto naked ApoA-I to make pre beta HDL particles
- ABCA1 forms homodimers and interacts with lipid free Apo A-I to form a particle that has a disk shape
- this disk shape which now has lipids dissociates into the circulation from ABCA1 since it has lipids
- discoidal HDL
what is the second stage of HDL transport?
LCAT esterifies the cholesterol inside the discoidal HDL
it uses a fatty acid from phosphatidylcholine
this cholesterol ester is now neutral, so it has to hide inside the HDL, which then becomes of the shape of a ball instead of a disk
what is the third stage of HDL transport?
- CETP (cholesterol ester transfer protein)
- acts upon HDL3, interacts with VLDL (triglyceride rich)
- the TG from VLDL interact with HDL3 via CETP (banana shape but it is a tube)
- you can transport neutral lipids through the tube (middle is hydrophobic), such as CE and TG
- the CE and TG will go down the concentration gradients, switch sides
what is the product of the CETP reaction?
HDL2 (final form of HDL)
what is the last stage of HDL transport?
- now HDL2 has the configuration and is expressing the right epitope from ApoA1 that it can now interact with liver receptor SRB1
- SRB1 has a specificity, interacts with ApoA1 when it is super lipidated
- HDL empties its contents into the liver
- what is left is a poorly lipidated ApoA1-> will go back to bind with ABCA1
what do the two forms of ApoA1 have affinities for?
- ApoA1 unlipidated=high affinity for ABCA1
- ApoA1 highly lipidated=high affinity for SRB1
what does the liver make with excess lipids?
- with excess lipids you make VLDL and bile
what are the three components that make up bile?
bile salts
cholesterol
phosphatidylcholine
how are bile salts made and what are they?
glycocholate
taurocholate
made from cholesterol by Cyp7alpha 1
what is the rate limiting step for the synthesis of bile?
Cholesterol 7 alpha hydroxylase is the rate limiting step for the synthesis of bile
what are consequences of dyslipidemias?
build up of excess fat
show up in eyes, under eyes, on skin
also cardiovascular side effects
what is “good” and what is “bad” cholesterol?
good=HDL
bad=LDL
what is atherosclerosis and what does it lead to?
- overabundance of LDL: LDL in arterial wall infiltrates it
- macrophages are going to engulf those extra LDL and try to return extra cholesterol to liver
- those macrophages become foam cells, filled with lipids so much that they do apoptosis
- this triggers an immune response to clear out those debris and phenomenon amplifies
- eventually you build a plaque, macrophages are unable to eliminate excess LDL
- this blocks artery and causes high BP
- can rupture, when its in the coronary arteries, prevents oxygen from feeding the muscle (in complex IV), and parts of the heart muscle will die
- this leads to disregulated heart beating
what happens if you have an LDL plaque in the brain?
- if you have the same thing in the brain: clot detaches and blocks small artery in the brain
- this kills that part of the brain and causes a stroke
what is the normal pathway?
cells intake LDL through LDL receptors
excess cholesterol is brought back to the membrane and effluxed onto HDL (on ApoA1) by ABCA1 transporter
what happens if you have an LDL receptor defficiency?
too much LDL in the blood
high CVD risk
what happens if you have an ABCA1 defficiency?
too little HDL
high CVD risk
