Cholesterol Flashcards
What are the main functions of lipids?
- energy storage
- component of cell membranes
- required to solubilise fat-soluble vitamins
- biosynthetic precursors
- signalling molecules
How much cholesterol comes from the diet?
25% of the cholesterol in the body comes from the diet
The liver also synthesises cholesterol
How is cholesterol transported in the blood plasma?
It is insoluble in the liquid blood plasma
It is transported by a lipoprotein
What are lipoproteins?
They are particles found in the plasma that will transport ANY type of lipid
How are do lipoproteins differ from one another?
They all share a general structure
They have different ratios of proteins to lipids
How are lipoproteins classified?
According to their density and chemical properties
What is the largest and least dense lipoprotein?
What is its role and where is it synthesised?
The chylomicron
It is synthesised in the intestines
They carry dietary fats from the intestine to the tissue
What is VLDL?
Where is it synthesised?
Very low density lipoprotein
It is synthesised in the liver
What is the role of VLDL?
It transports lipids from the liver into the tissues
This includes the transport of cholesterol
What is LDL?
Where is it synthesised?
Low density lipoprotein
LDLs are derived from VLDLS
What is the role of LDL?
It is the main carrier of cholesterol around the body
It transports cholesterol to the peripheral tissues
What is HDL?
Where is it synthesised?
High density lipoprotein
Formed in the blood
What is the role of HDL?
It transports cholesterol from the peripheral tissues back to the liver for degradation
What is found in the external monolayer of lipoproteins?
- apolipoproteins
- free cholesterol
- phospholipids
What is found in the core of lipoproteins?
- esterified cholesterol
2. triacylglycerols
What is responsible for distinguishing the functions of each lipoprotein?
The apolipoproteins
Why is it important to distinguish the function of each lipoprotein?
It allows the determination of the start and end-points for cholesterol and lipid transport to particular tissues
What are the major classes of apolipoproteins?
- ApoA
- ApoB
- ApoC
- ApoE
There are subclasses of ApoA, B and C
What are the roles of ApoA?
- major component of HDL that allows HDL to be recognised
2. mediates efflux of cholesterol from peripheral cells and influx to the liver
What are the roles of ApoB?
It recognises apoB (LDL) and apoE receptors
It facilitates the uptake of LDL
What is the role of ApoC?
activator of lipoprotein lipase
This breaks down fats for energy or storage
What is the role of ApoE?
It stabilises VLDL for cellular uptake
It is a ligand for the apoB/E (LDL) receptor
What regulates apoplipoprotein synthesis?
Where are they synthesised?
Apolipoprotein synthesis is regulated by dietary fat intake
Ingesting fat stimulates their production
They are synthesised in the intestine
What stimulates synthesis of apolipoproteins in the liver?
The influence of hormones and drugs
e.g. insulin, glucagon, sex hormones
What apolipoproteins are involved in regulating key enzymes in lipoprotein metabolism?
apoC-II regulates lipoprotein lipase
apoA-1 regulates lecithin-cholesterol acyltransferase (LCAT)
How do apolipoproteins allow lipoproteins to be targeted to the correct tissues?
Apolipoproteins are ligands for interactions with lipoprotein receptors
apoB100 and apoE for LDL receptors
apoA-I for HDL receptors
What is the structure of LDL?
It has a single strand of ApoB running around the exterior
It has a hydrophobic core of triacylglycerols and cholesterol esters
What is the problem with LDL being susceptible to oxidation?
The oxidative form of LDL is responsible for forming atherosclerotic plaques
What is the structure of HDL?
It has 2 ApoA strands
ApoA I and ApoA II
What is the function of the ApoA strands in HDL?
They protect the HDL particle from undergoing oxidative modifications
Why does the blood appear milky after eating a meal high in fat?
This is due to the abundance of chylomicrons
These are made in the intestine and transport triglycerides and cholesterol in the blood
What is the action of lipoprotein lipase?
It hydrolyses triglycerides to fatty acids
They are taken up by target tissues and used for energy production or storage
What happens once the chylomicrons have released their triglycerides?
They shrink and the remnants are transported back to the liver
What happens to VLDLs once they have been made by the liver?
They transport lipids to their target tissues
They are acted on by lipoprotein lipase to release fatty acids
What happens to VLDL remnants once they have released their lipids?
They remain in the blood and become LDL
How does the liver primarily dispose of cholesterol?
In the form of bile salts
How do lipoproteins enter cells?
They cannot enter cells without a receptor
Membrane-bound receptors allow allow cholesterol to enter hepatic and peripheral cells
What will the LDL receptor bind to?
This is the ApoB/E receptor
It will bind to apoB100 or apoE
What regulates LDL receptor gene expression?
Intracellular cholesterol concentration
If cells have a high level of cholesterol, they will stop making receptors
What happens once LDL binds to the LDL receptor?
It stimulates receptor-mediated endocytosis
What happens to LDL and its receptor in the endosome?
LDL is released from the receptor in the endosome
The receptor is recycled to the plasma membrane
The cholesterol is then released and used within the cell
What happens to the LDL particle once the ApoB-100 protein has bound to the receptor?
The LDL particle is taken in via a clathrin coated pit
The clathrin-coated vesicle will then form
What happens once the clathrin-coated vesicle forms?
The clathrin dissociates into clathrin triskelions
The LDL with the receptor is still in the vesicle
What is the change in pH in the uncoated vesicle?
What happens when the pH changes?
It goes from pH 7 to pH 5
The receptor begins to be nipped off in a separate vesicle
When will the recycled LDL receptors be re-expressed?
When the cell requires cholesterol
What happens to LDL receptors when there is high intracellular cholesterol?
This suppresses LDL receptor synthesis
This prevents excessive uptake of cholesterol by cells
Excess cholesterol remains in the blood as LDL
What does high blood levels of HDL correlate with?
Low incidence of atherosclerosis
Why is HDL known as “good cholesterol”?
It scavenges cholesterol from cells and other lipoproteins
It returns it to the liver to be excreted in the bile
Which process allows HDL to protect against atherosclerosis?
reverse cholesterol transport
How does HDL become mature HDL?
- nascent HDL has a huge capacity to extract cholesterol from cells
- once it has extracted cholesterol, it becomes cholesterol-laden mature HDL
What happens to the mature HDL after it has extracted cholesterol?
It returns to the liver and binds to a scavenger receptor
Cholesterol esters are converted back into free cholesterol which is secreted in bile
What are dyslipidaemias?
Inherited diseases that are NOT related to lifestyle or diet
What causes familial hypercholesterolaemia?
Mutations affecting the LDL receptor
This means that cells cannot take up LDL
What happens if cells cannot take up LDL?
There is an increased amount of circulating LDL
Excess cholesterol is deposited in the arteries, increasing risk of atherosclerosis
Why is cholesterol essential?
- it is a structural component of cell membranes
2. it is needed for synthesis of bile acids, steroid hormones and fat-soluble vitamins (A, D, E and K)
What are high serum levels of cholesterol indicative of?
The risk for cardiovascular disease
What are the cardiac manifestations of atherosclerosis?
- chest pain
- palpitations
- heart attack
What happens if atherosclerosis occurs in cerebral arteries?
It can lead to stroke of cerebral haemorrhage
What does peripheral atherosclerosis lead to?
- pain
- ischaemia
- ulceration and gangrene
What is the first stage in the development of plaques?
A fatty streak develops around age 20
This is independent of lifestyle and develops in everyone
What will the fatty streak progress to and what is this dependent on?
it progresses to a fibrous plaque
This is cholesterol-laden
It depends on age and lifestyle
What happens once the fibrous plaque has formed?
The plaque is now depositing in the lumen of the artery
It will advance to an advanced plaque which shows complete occlusion
How does the plaque cause heart attacks/stroke?
When the plaque ruptures, the blood will clot and cause thrombosis
Why are statins taken at night?
Cholesterol is made in the liver
This process occurs overnight whilst we are sleeping
What molecule is a precursor for the liver to make cholesterol?
How is this formed?
Mevalonate
This is formed from HMG-CoA by the action of HMG-CoA reductase
What is the synthetic pathway involved with cholesterol formation?
- HMG-CoA
- Mevalonate
- IPP
- FPP
- Squalene
- Cholesterol
What are the two organs that primarily control blood cholesterol levels?
- Liver produces cholesterol and bile acids
2. Intestine absorbs cholesterol from food and bile
How do statins affect the liver?
they prevent cholesterol synthesis in the liver
What is the role of cholesterol absorption inhibitors?
What is an example?
They prevent the uptake of cholesterol from the intestine
e.g. ezetimibe
How do plant sterols act as a cholesterol absorption inhibitor?
The plant sterols are taken up preferentially
The cholesterol remains in the intestine and is excreted
What is the role of fibrates?
What are examples?
They reduce triglycerides and increase HDL
e.g. gemfibrozil and fenofibrate
How do statins work?
They inhibit HMG-CoA reductase
This means that HMG-CoA cannot be converted to mevalonate
They lower plasma cholesterol levels by decreasing cholesterol synthesis
When statins are used, what is the result of lowering intracellular cholesterol levels?
There is increased expression of the LDL receptor
More LDL receptors increase the uptake of cholesterol from the blood
What is a pleiotropic effect?
It is an action of a drug, other than those for which the agent was specifically developed
This may be an undesirable side effect or a beneficial effect
What is the pleiotropic effect of statins?
FPP is converted to GGPP
This cannot occur if statins are being taken
What type of molecules are FPP and GGPP?
What is their role?
They are isoprenoids
They make a tail for small G-proteins, such as Ras and Rho
What are Ras and Rho?
Signalling molecules that control gene expression
What must happen to small G-proteins before they can perform any cell signalling activity?
They must be prenylated through the attachment of FPP or GGPP
The isoprenoid lipid tail attaches the small G protein to the membrane
What is the difference in the way Ras and Rho are prenylated?
Ras is farnesylated (attached to FPP)
Rho is geranylgeranylated (attached to GGPP)
What is the problem with some of the signalling pathways activated by Ras and Rho?
They can lead to actions in the cell that may be supportive of cardiovascular disease
e.g. thrombosis, production of inflammatory molecules
How may statins work to decrease the risk of cardiovascular disease?
They inhibit synthesis of cholesterol and isoprenoids
What is the enzyme that converts FPP to squalene in the liver?
Squalene synthase
What are the 4 pleiotropic effects of statins?
- improved endothelial dysfunctin
- antioxidant properties
- inhibition of inflammatory responses
- stabilising atherosclerotic plaques
What is PCSK9?
Proprotein convertase stubtilisin/kexin type 9
It is a protease enzyme expressed by the liver and intestine
What is the role of PCSK9?
It promotes degradation of the LDL receptor inside the cell
This prevents recycling of the LDL receptor to the cell surface
How does PCSK9 enter the cell?
- it binds to the receptor that has bound LDL carrying cholesterol
- it is taken up with the receptor
What is the action of PCSK9 once it is inside the cell?
It degrades the LDL receptor so it cannot be recycled to the membrane
This decreases LDL uptake
What are PCSK9 inhibitors?
Antibodies that will mop up any PCSK9 in the blood
This allows the LDL receptor to be internalised and recycled
What is increased PCSK9 concentration associated with?
Increased risk of cardiovascular disease and hypercholesterolaemia
