Lecture 4 - Lipid Transport Flashcards
briefly outline what transports lipid in the blood
2% are transported by albumin
98% transported by lipoprotein particles
what is the general structure of lipoproteins ?
Integral Apolipoproteins
(e.g. apoA, ApoB)
Peripheral Apolipoproteins
(e.g. apoC, ApoE)
Phospholipid monolayer with small amount of cholesterol
Cargo consisting of:
• Triacylglycerol
• Cholesterol ester (cholesterol linked to fatty acid)
• Fat soluble vitamins (A,D,E&K)
what are the classes of proteins ?
chylomicrons
VLDL - very low density lipoproteins
IDL - intermediate density lipoproteins
LDL - Low density lipoproteins
HDL - High Density lipoproteins
VLDLs can degrade to IDLs which can degrade to HDLs
Each contains variable content of apolipoprotein, triglyceride, cholesterol and cholesterol ester
Main carriers of fat - Chylomicron and VLDL
Main carriers of cholesterol esters - IDL, LDL, HDL
how does lipoprotein density link to diameter ?
the larger diameter - the lower density
chylomicrons - largest and lowest density
followed by VLDL, IDL, LDL, HDL (most dense) respectivly
Apolipoproteins - What are they ?
particles that attach to lipoproteins
A,B,C,D,E,H
apoB - VLDL, IDL and LDL
apoAI - HDL
they can be integral or peripheral
they provide structural integrity, help packing of water insoluble lipids.
are co factors for enzymes
and act as ligand cell surface receptors
outline the metabolism of chylomicrons
probably best to draw this again - as will ALL of metabolsim
food is broken down into fats, and absorbed in the small inestine, where it is packaged into chylomicrons. and apoc - 48 is added
here it enters the lymphatic system, before entering the blood where it gains apoE and apoC via the left sublcavian vein in the thoracic duct
lipoprotein lipase binds apoC will break down the fats into fatty acids and glycerol
apoC-II is a cofactor of lipoproteins lipase
the fatty aics will either be used by the muscles for energy, or stored as TAG’s in adipose tissue
chylomicron remnants will undergo receptor mediated endocytosis via apoE recog to enter the liver, where lysosomal degregaiton of remaining contents occurs
this prodices fattys acids, cholesterol and glycerol, glycerol from the blood also feed into the liver
explain vldl metabolsim
VLDL made in liver for purpose of transporting
triacylglycerol (TAG) to other tissues.
• Apolipoprotein apoB100 added during formation and
apoC and apoE added from HDL particles in blood.
- VLDL binds to lipoprotein lipase (LPL) on endothelial cells in muscle and adipose and starts to become depleted of triacylglycerol
- In muscle the released fatty acids are taken up and used for energy production
• In adipose the fatty acids are used for re-synthesis of
triacylglycerol and stored as fat
expalain IDL and LDL metabolim
Formation
• VLDL degrades –> IDL degrades —> LDL
• As triacylglycerol content of VLDL particles drops some, VLDL particles dissociates from the LPL enzyme
complex and return to liver
• If VLDL content depletes to ~30%, the particle
becomes a short-lived IDL particle.
• IDL particles can also be taken up by liver or rebind to
LPL enzyme to further deplete in TAG content
• Upon depletion to ~ 10%, IDL loses apoC & apoE and
becomes an LDL particle (high cholesterol content)
Primary function of LDL is to provide cholesterol from liver to peripheral tissues.
• Peripheral cells express LDL receptor and take up LDL via process of receptor mediated endocytosis
• Importantly, LDL do not have apoC or apoE so are not efficiently cleared by liver (Liver LDL-Receptor has a high affinity for apoE).
Clinical relevance
• Half life of LDL in blood is much longer than VLDL or IDL making LDL more susceptible to oxidative damage
• Oxidised LDL taken up by macrophages that can transform to foam cells and contribute to formation of atherosclerotic plaques - angina, heart attack, stoke, thrombus formation
draw the VLDL, IDL and LDL metabolsim system
check session 2 lec 2 pg 16
how are fatty livers in alcholics linked to lipoproteins ?
they cannot make enough lipoproteins to remove all the fatty acids from the liver, so it becomes fatty
this is as they do not have enough proteins
how does LDL enter the cells, and what is its fate ?
- Cells requiring cholesterol express LDL receptors on plasma membrane
- apoB-100 on LDL acts as a ligand for these receptors
- Receptor/LDL complex taken into cell by endocytosis into endosomes
- Fuse with lysosomes for digestion to release cholesterol and fatty acids
- LDL receptor expression controlled by cholesterol concentration in cell
explain HDL metabolism
get the braod strokes here not the details
also draw it, check - session 2, lec 2 - pg 20
Nascent HDL synthesised by liver and intestine
(low TAG levels)
- HDL particles can also “bud off” from chylomicrons and VLDL as they are digested by LPL
- Free apoA-I can also acquire cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent-like HDL
Maturation
• Nascent HDL accumulate phospholipids and cholesterol from cells lining blood vessels
• Hollow core progressively fills and particle takes on more globular shape
• Transfer of lipids to HDL does not require enzyme activity
reverse cholesterol transport
HDL have ability to remove cholesterol from cholesterol-laden cells and return it to liver
- Important process for blood vessels as it reduces likelihood of foam cell and atherosclerotic plaque formation
- ABCA1 protein within cell facilitates transfer of cholesterol to HDL. Cholesterol then converted to cholesterol ester by LCAT
Fate of mature HDL
• Mature HDL taken up by liver via specific receptors
• Cells requiring additional cholesterol (e.g. for steroid hormone synthesis) canalso utilise scavenger receptor
(SR-B1) to obtain cholesterol from HDL
• HDL can also exchange cholesterol ester for TAG with VLDL via action of cholesterol exchange transfer protein (CETP)
outline the functions of the different lipoproteins
Chylomicrons - Transport dietary triacylglycerol from the intestine to tissues such as adipose tissue.
VLDL - Transport of triacylglycerol synthesised in liver to adipose tissue for storage.
IDL - Short-lived precursor of LDL. Transport of
cholesterol synthesised in the liver to tissues.
LDL- Transport of cholesterol synthesised in liver to
tissues.
HDL- Transport of excess cholesterol from cells to liver
for disposal as bile salts and to cells requiring
additional cholesterol
what are hyperlipoproteinaemias ?
a raised plasma level of one or more protein classes - caused by over production or under removal
6 classes
to know
I - defective LDP
IIa - Defective LDL receptor
III - defective apoE
Clinical signs
- High level of cholesterol in blood
- Cholesterol depositions in various areas of body
- Xanthelasma - Yellow patches on eyelids
- Tendon Xanthoma - Nodules on tendon
- Corneal arcus - obvious white circle around eye. Common in older people but if present in young could be a sign of hypercholesterolaemia
what are the consequences of raised serum LDL
Oxidised LDL
Recognised and engulfed by Macrophages
Lipid laden macrophages called Foam cells accumulate in intima of blood vessel walls to form a fatty streak
Fatty streaks can evolve into atherosclerotic plaque
Grows and encroaches on the lumen of the artery
can cause angina or rupture to become a thrombosis (clot) - causes MI or stroke
