Lipid Transport Flashcards
What are the different groups of lipids
Triacylglycerol - Diaclyglycerol, & Monoacylglycerol
Fatty acids
Cholesterol - Cholesterol esters
Phospholipids
Vitamins A, D, E, and K
How are lipids transported, and why is it transported like that
- Structurally diverse group of compounds
- Hydrophobic molecules insoluble in water = Problem for transport in
blood! - Solution- transported in blood bound to carriers
- ~ 2% of lipids (mostly fatty acids) carried bound to albumin but this has a limited capacity (~ 3 mmol/L)
- ~ 98% of lipids are carried as lipoprotein particles consisting of phospholipid, cholesterol, cholesterol esters, proteins & TAG
What is the Plasma concentration of Cholesterol and Glucose
-Glucose has a conc of 5mmol/L
-Cholesterol has a conc of <5mmol/L
Total lipid plasma conc, and why is this figure surprising
Total lipids
4000 - 8500 mg/L
Higher than expected as lipids are insoluble in water
Why are phospholipids important
They make plasma membranes
What is the structure of phospholipids
- Phospholipids have a Glycerol backbone,
- That attaches to two fatty acids (Non Polar & Hydrophobic tails)
- Third carbon in glycerol attaches to polar (hydrophilic) head via phosphate
The polar head can either be
Choline –> phosphatidylcholine - MAJORITY
Inositol –> phosphatidylinositol - MINORITY
STRUCTURES that can be made from phospholipids
Bilayer sheets - Membranes of organelles & Lipid membrane Bilayers
Liposome - Allows for there creation of different cellular environments
Micelle - Allows for the creation of Lipoprotein particles
How much cholesterol is needed a day
What happens if don’t get enough in our diet.
1 g is needed a day, if we don’t get this from our diet the liver will synthesis the addition cholesterol that is required.
What is cholesterol used for
- Essential component of membranes (modulates fluidity)
- Precursor of steroid hormones
- Cortisol
- Aldosterone
- Testosterone
- Oestrogen
- Precursor of bile acids
How is cholesterol transported around the body
Transported around body as cholesterol ester
This is the addition of a fatty acid tail to the cholesterol,
Using the enzyme (LCAT) or Acyl-coenzyme A (cholesterol acyltransferase)
Then moves by Lipoprotein
What is the function of Lipoproteins
Transporting Lipids around the body
What is the Cargo of Lipoprotein
- Triacylglycerol
- Cholesterol ester (cholesterol linked to fatty acid)
- Fat soluble vitamins (A,D,E&K)
What are Peripheral Apolipoproteins
What are Integral Apolipoproteins
- Peripheral They associate with lipoproteins
- Intergral pass though phospholipid membrane
What are the 5 classes of Lipoproteins
- Chylomicrons
- Transport Dietary Fats
- VLDL (Very Low Density Lipoproteins)
- Transports Fats made in liver
- IDL (Intermediate Density Lipoproteins)
- Produced when VLDL becomes metabolised / Depletes
- LDL (Low Density Lipoproteins)
- When further depletion of VLDL and IDL occurs LDL is produced
- HDL (High Density Lipoproteins)
- Trasnports excess cholesterol from cells to liver
Which classes of lipoproteins are the main carrier or fats and the main carriers of cholesterol esters
MAIN CARRIERS OF FATS
- Chylomicron and VLDL
MAIN CARRIERS OF CHOLESTEROL ESTERS
- IDL, LDL & HDL
How do you separate different Lipoproteins
What is the relationship between Density and Diameter of lipoproteins
Ultracentrigugation
* Density measured by flotation ultracentrifugation
- Particle diameter inversely proportional to density
(less protein in % in larger diameter)
What are Apolipoproteins
What is their role
- Each class of lipoprotein particle has a particular complement of associated proteins (apolipoproteins)
- Apolipoproteins can be integral passing through phospholipid bilayer or peripheral “resting” on top
- Have two roles:
- Structural:
Packaging water insoluble lipid - Functional:
Co-factor for enzymes
Ligands for cell surface receptors
What are the Six major classes of Apolipoproteins
Six major classes (A,B,C,D,E & H)
Put lipoproteins in order from most dense to least
HDL < LDL < IDL < VLDL < Chylomicrons
function of chylomicrons
transport dietary triacylglycerol from the intestine to tissues such as adipose tissue
function of VLDL
transport of triacylglycerol synthesised in liver to adipose tissue for storage
function of IDL
short lived precursor of LDL
transport of cholesterol synthesised in the liver to tissues
function of LDL
transport of cholesterol synthesised in liver to tissues
function of HDL
transport of excess cholesterol from cells to liver for disposal as bile salts and to cells requiring additional cholesterol
chylomicron metabolism
- dietary lipid hydrolysed by pancreatic lipase in small intestine and apoB-48 added before entering lymphatic system
- travel to the thoracic duct which empties into left subclavian vein and acquire apoC and apoE once in blood
- apoC binds lipoprotein lipase on adipocytes and muscle which releases fatty acids enter cells depleting. chylomicron of its fat content
what happens when the triglyceride in the chylomicron is reduced to -20%?
apoC dissociates and chylomicron becomes chylomicron remnant
what happens to the chylomicron remnants?
return to liver
LDL receptor on hepatocytes binds apoE and chylomicron remnant taken up receptor mediated endocytosis
lysosomes are release to degrade remaining contents
Where is VLDL made?
liver
VLDL metabolism
- particles made in liver
- apoB100 is added during formation and apoC and apoE are later added from HDL particles in blood
- VLDL binds to LPL and starts to become depleted of triacylglycerol
how does the muscle use the product of VLDL metabolism
the released fatty acids are taken up and used for energy production
how does the adipose tissue use the product of VLDL metabolism
fatty acids are used for re synthesis of triacylglycerl and stored as fat
how is IDL particle formed?
VLDL content depletes to -30% the particle becomes a short lived IDL particle
what happens to the VLDL as the triacylglycerol content drops?
some VLDL particles dissociates from the LPL enzyme complex and return to liver
what happens to the IDL particle?
can also be taken up by the liver or rebind to LPL enzyme to further deplete in TAG content
how is LDL formed?
upon depletion to -10% of IDL
IDL loses ApoC and ApoE and becomes an LDL particle
What is the Functions of LDL’s
Function
* 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).
how can atherosclerotic plaques form from LDL?
(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
what happens to LDL?
peripheral cells express LDL receptor and take up LDL via receptor mediated endocytosis
lysosomal degradation occurs which releases cholesterol, fa, glycerol
how does LDL enter cells?
by receptor mediated endocytosis
cells requiring cholesterol express LDL receptors on plasma membrane
apoB-100 on LDL acts as a ligand for the receptors
receptor/LDL complex taken into cell by endocytosis into endoscopes
fuses with lysosomes for digestive to release cholesterol and fatty acids
synthesis of HDL metabolism
- synthesised by liver and intestine
- HDL particles can also bud off from chylomicrons and VLDL as they are digested by LPL
- free apoA-I can also aquire cholesterol and phospholipid from other lipoproteins and cell membrane to form HDL
Maturation of HDL
HDL accumulate phospholipids and cholesterol from cells lining blood vessels
hollow core progressively fills and particles takes on more globular shape
reverse cholesterol transport
HDL have the ability to remove cholesterol from cholesterol-laden cells and return it to liver
ABCA1 protein within cell facilitates transfer of cholesterol to HDL
cholesterol then converted to cholesterol ester by LCAT
Fate of mature HDL
the mature HDL is taken up by liver via specific receptors
Cells requiring additional cholesterol can also utilise scavenger receptor to obtain cholesterol from HDL
Hal can also exchange cholesterol ester for TAG with VLDL via action of cholesterol exchange transfer protein
What is hyperlipoproteinemia?
raised plasma level of one or more lipoprotein classes
what causes hyperlipoproteinemia?
over production
under removal
what defects cause hyperlipoproteinemia?
defects in enzymes, receptors and apoproteins
clinical signs of hypercholesterolaemia?
high levels of cholesterol in blood
cholesterol deposits in various areas of the body
xanthelasma- yellow patches on eyelids
tendon Xanthoma- nodules on tendon
corneal arcus- obvious white circle around eye in young people
plaque formation
- oxidised LDL
- recognised and engulfed by macrophages
- foam cells accumulate in intimate of blood vessel walls to from a fatty streak
- fatty streaks can evolve into atherosclerotic plaque
- grows and encroaches on the lumen of the artery
- ruptures
- triggers acute thrombosis by activating platelets and clotting cascade which leads to stroke or heart attack
treatment for hyperlipoproteinemia
diet- reduce cholesterol and saturated lipids, increase fibre
liferstyle- increase exercise, stop smoking
statins- reduce cholesterol synthesis by inhibiting HMG-CoA reductase
bile salt sequestrants- bind bile salts in GI tract, forcing liver to produce more bile acids using more cholesterol
statins mechanism of action
inhibits HMG-/CoA reductase enzyme activity, which decreases cholesterol synthesis
Why is LDL considered bad cholesterol
- As They have a large half life
- Higher change of oxidised LDL
- Recognised and engulfed by Macrophages, over time they become
- 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, this can cause Angina (hearts can gets nutrient it needs)
- Ruptures
8.Triggers acute thrombosis (clot) by activating platelets and clotting cascade - Stroke - Ruptures in bran
Myocardial infarction - Heart attach if one of the coronary arteries
What is PCSK9 inhibitors
- PCSK9 promotes the breakdown of LDL receptors in liver cells
- Inhibiting the PCSK9 protein results in more LDL receptors being recycled and therefore more LDL particles removed from blood. This lowers plasma cholesterol level
What are the tests results you get form cholesterol
- Total Cholesterol (TC) Ideally 5 mmol/L or less
- Non HDL-Cholesterol (total cholesterol minus HDL-cholesterol) Ideally 4 mmol/L or less
- LDL-Cholesterol (LDL-C) Ideally 3 mmol/L or less
- HDL-Cholesterol (HDL-C)
Ideally over 1 mmol/L (men) and over 1.2 mmol/L (women).
- Total cholesterol:HDL-C ratio
Ratio above 6 considered high risk - the lower the ratio the better. - Triglyceride (TG) Ideally < 2 mmol/L in fasted sample
