Lipid Transport Flashcards
Define the term ampiphatic
- Both hydrophobic and hydrophilic properties e.g. Phospholipids
- Polar and non-polar regions
Describe the formation of a MICELLE
- Phospholipids coalesce in water to form a globular structure
- Hydrophilic polar heads around the outside and hydrophobic non-polar tails on the inside
What is the difference between a MICELLE and a LIPOSOME?
Liposome is formed from a BILAYER of phospholipids (micelle is UNILAYERED)
Where does the cholesterol in our body originate from?
- Obtained from diet
- Synthesised in the liver from HMG-CoA reductase
Why is cholesterol important?
- Essential component of membranes (fluidity)
- Precursor of steroid hormones
- Precursor of bile acids
What is a cholesterol ester and how is it formed?
- Cholesterol is transported around the body as cholesterol esters
- Cholesterol molecule esterified with a fatty acid
- Catalysed by CHOLESTEROL ACYLTRANSFERASE
List 3 components of a lipoprotein
- Phospholipid monolayer (contains small amount of cholesterol)
- Cargo containing TAGs, cholesterol esters and fat soluble vitamins
- APOLIPOPROTEINS (peripheral on outside and integral which can pass through monolayer)
What are the 5 classes of lipoproteins?
- Chylomicrons
- VLDLs
- IDLs
- LDLs
- HDLs
Which lipoproteins are the main carriers of FAT?
- Chylomicrons
- VLDLs
Which lipoproteins are the main carriers of CHOLESTEROL ESTERS?
- IDLs
- HDLs
- LDLs
How could you tell if chylomicrons were present in blood?
- Form a ‘creamy layer’ on top of blood
- Usually only present up to 4-6hrs after a meal
What determines the density of the lipoprotein?
- % protein content (more protein = more dense)
- diameter (smaller diameter = higher density as they are inversely proportional)
What are the structural and functional roles of apolipoproteins?
- STRUCTURAL - packaging water insoluble lipid
- FUNCTIONAL - cofactors for enzymes; Ligands for cell surface receptors
How do chylomicrons enter the blood stream?
- Loaded with Fats, cholesterol and vitamins in small intestine and enter lymphatic system
- Travel to thoracic duct and enter blood through LEFT SUBCLAVIAN VEIN (avoids the liver)
When do chylomicrons acquire apoC and apoE apolipoproteins?
On entering the blood stream from the lymphatic system
What is the role of apoC in chylomicron metabolism?
- Binds to LIPOPROTEIN LIPASE on adipocytes and muscle cells
- Triggers the release of contents from chylomicron to the cells, depleting the fat contents of the chylomicron
- TAGs can then be used by cells (either stored or metabolised)
What is a chylomicron remnant?
Formed when fat contents of chylomicron have been depleted to ~20% (emptied at muscle cells and adipocytes)
What is the role of apoE in chylomicron metabolism?
- apoE on chylomicron remnant binds to LDL receptor on hepatocytes and initiates receptor mediated endocytosis
- Broken down by lysosomes and remaining fat content is released (used for metabolism)
Where is lipoprotein lipase found?
Capillary walls of adipocytes and muscle cells
How are LDLs formed from VLDLs?
- VLDLs bind to lipoprotein lipase (LPL) at cells and deplete stores of TAGs
- When stores deplete to ~30% -> becomes IDL particle
- IDL further depletes stores of TAGs until ~10% where IDL loses apoC and apoE and becomes an LDL
- LDL has a high cholesterol content
Why do lipids need to be bound to carriers in order to me transported?
- HYDROPHOBIC
- INSOLUBLE in water so cannot travel freely in blood
Why do LDLs remain in the blood longer than other lipoproteins?
- Do not have apoC or apoE so are not efficiently cleared by the liver
- More susceptible to oxidative damage if they remain in blood
- Oxidsied LDLs are taken up by macrophages to form foam cells —> atherosclerosis
What is the main function of LDLs and how is this achieved?
- Primary function is to provide cholesterol to peripheral tissues from liver
- LDLs bind to LDL receptors on peripheral cells and are taken up by receptor mediated endocytosis
What is RECEPTOR MEDIATED ENDOCYTOSIS?
Binding of ligand (e.g. apoB-100) of molecule (LDL) to cell surface receptor triggers the endocytosis of the molecule-receptor complex into cell in the form of an ENDOSOME
Explain how receptor mediated endocytosis is used in the entering of LDL into cells
- Cells express LDL receptor on plasma membrane
- apoB-100 on LDL is a ligand for this receptor so binds to receptor forming RECEPTOR/LDL COMPLEX which then enters the cell by endocytosis
State 3 ways in which HDLs can be synthesised
- Nascent HDL syntheised in LIVER
- “Bud off” from chylomicrons/VLDL as they are digested by LPL
- Free apoA-1 can acquire cholesterol and phospholipids from other lipoproteins to form nascent-like HDL
How do HDL particles mature?
- Hollow core progressively fills as nascent HDL accumulate phospholipids and cholesterol from cells
- Particle becomes more globular
- Transfer of lipids to HDL does NOT require LPL
What is the main role of HDLs?
Transport of EXCESS cholesterol from tissues to liver for disposal as bile salts or for cells that require additional cholesterol (steroidogenic cells)
How do cells attain additional cholesterol from HDLs?
- Utilise SCAVENGER RECEPTOR (SR-B1)
- Cholesterol used for steroid hormone synthesis
Describe the action of cholesterol exchange transfer protein (CETP)
HDL can exchange cholesterol ester for TAGs with VLDL particles in blood
What is the main role of VLDLs?
Transport of triacylglycerols (TAG) syntheised in liver to adipose tissue for storage
What are the clinical signs of HYPERCHOLESTEROLAEMIA?
- High level of cholesterol in blood
- Cholesterol deposits in various areas of body (e.g. eyelids, tendons, white circle around eye)
Describe the formation of foam cells
- LDL in blood becomes OXIDISED by ROS (lipid peroxidation)
- Recognised by macrophages which engulf oxidised LDL
- Macrophages become lipid-laden, forming foam cells
Explain how the formation of an atherosclerotic plaque can lead to thrombosis
- Foam cells accumulate in INTIMA of blood vessel wall forming a fatty streak which evolves into a plaque
- Growth of plaque ENCROACHES lumen of vessel, restricting blood flow
- Plaque RUPTURES, triggering acute thrombosis
Explain the treatment methods for hyperlioproteinaemia
- DIET modifications like reducing cholesterol and saturated fats; increasing fibre intake
- LIFESTYLE changes e.g. More exercise, stop smoking
- DRUG usage such as Statins and Bile Salt Sequestrants
How do Statins help to reduce cholesterol?
Inhibit HMG-CoA reductase, an important enzyme in the synthesis of cholesterol from mevanolate
What are the clinical consequences of atherosclerosis?
Encroaching of lumen of arteries can cause various diseases such as MI, STROKE and ANGINA
Explain how increasing dietary fibre may help in lowering cholesterol
- Interferes with reabsorption of bile salts in GI tract
- Liver is encouraged to make more bile salts, using cholesterol to do so
Why might Statins cause side effects?
- Inhibits HMG-CoA reductase (very early on in cholesterol synthesis)
- Important intermediates produced during the synthesis of cholesterol cannot be formed
What is the role of the ABCA1 protein?
- REVERSE CHOLESTEROL TRANSPORT
- Facilitates the transport of cholesterol from HDL particles inside cell
- Cholesterol is converted to cholesterol esters using LCAT
What is dyslipoproteinaemia?
Any defect in the metabolism of the plasma lipoproteins
What characterises hyperlioproteinaemia?
Raised levels of one or more of the plasma lipoproteins
