Lipid Transport Flashcards
Lipid transport
Lipids are -
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
Typical plasma lipid concentration ranges
TAGs - 0-2.0 mol/l Phospholipids ~2.5mmol/L Total cholesterol <5.0mmol/L Cholesterol esters ~3.5 mmol/L Free FA 0.3-0.8mmol/L
Phospholipids
Contain a non polar tail (hydrophobic) and a polar head (hydrophilic)
Classified by their polar head groups
Groups with a choline head are phosphatidylcholines and groups with a inositol head are phosphotidylinositol
e.g. PIP3 can act as an anchor in the membrane
Polar heads group linked by a phosphate to glycerol, followed by 2 FA tails where there are saturated or unsaturated
These can form bilayer sheet (sheet of phospholipids with tails in the midddle and heads on the outside), liposomes (same idea as a sheet but its a sphere (heads on the outside and the middle of the sphere)) or micelles (single layer of phospholipid (form a sphere with heads on outside and tails in the middle))
Cholesterols
Some cholesterol obtained from diet, but most synthesised in liver
Essential component of membranes (modulates fluidity)
Plus they are a Precursor of steroid hormones e.g. Cortisol, Aldosterone Testosterone and Oestrogen
Precursor of bile acids
Transported around body as cholesterol ester - cholesterol with a fatty acid group added to the end
Acetyl Co-A cholesterol acyltransferase or LCAT aids the conversion of cholesterol to cholesterol ester
Lipoproteins
These are lipid transporting proteins
Inside the lipoprotein beyond the micelle lipid wall is the cargo
Cargo can contain TGs, or cholesterol esters or Fat soluble vitamins (A,D,E and K)
On/in the surface of the lipoproteins are integral (apoA, apoB) and peripheral apolipoproteins (apoC,apoE)
Five distinct classes named according to density
1) Chylomicrons - used to transport dietary fats to the liver/tissues of use, usually only present in blood 4-6 hours after a meal
2) VLDL (Very Low Density Lipoproteins)
3) IDL (Intermediate Density Lipoproteins)
4) LDL (Low Density Lipoproteins)
5) HDL (High Density Lipoproteins)
Each contains variable content of apolipoprotein, triglyceride, cholesterol and cholesterol ester
Levels of lipoproteins in blood are of significant clinical importance
LDL is termed bad cholesterol - role in ATS, HDL is termed good cholesterol - helps remove cholesterol
Classification of Lipoproteins Is done on density -
Density obtained by flotation/ ultracentrifugation
Particle diameter inversely proportionate to density
Most dense and smallest of lipoproteins is HDL (5-15nM), largest and least dense of lipoproteins (VLDL (30-80nM) or chylomicron (100-1000nM))
Chylomicrons metabolism
Chylomicrons loaded in small intestine and apoB-48 added before entering lymphatic system
Travel to thoracic duct which empties into left subclavian vein and acquire 2 new apoproteins (apoC and apoE) once in blood.
apoC binds lipoprotein lipase (LPL) (hydrolyses TGs in lipoproteins) on adipocytes and muscle.
Released fatty acids enter cells depleting chylomicron of its fat content.
When triglyceride reduced to ~ 20%, apoC dissociates and chylomicron becomes a chylomicron remnant
Chylomicron remnants return to liver.
LDL receptor on hepatocytes binds apoE & chylomicron remnant taken up by receptor mediated endocytosis .
Lysosomes release remaining contents for use in metabolism
VLDL metabolism
VLDL made in liver for purpose of transporting triacylglycerol (TGs) 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
IDL and VLDL
Formation -
VLDL —>
LDL enters cells by receptor mediated endocytosis
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 –R expression controlled by cholesterol concentration in cell
HDL metabolism
Synthesis -
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
Fate of mature HDL -
Mature HDL taken up by liver via specific receptors
Cells requiring additional cholesterol (e.g. for steroid hormone synthesis) can also 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)
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
Hyperlipoproteinaemias
Raised plasma levels of 1 or more lipoprotein
Caused by either -
1) over production
2) under removal
6 main classes - defects in enzymes, receptors, apoproteins
Clinical Signs of Hypercholesterolaemia -
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
Raised serum LDL is associated with Atherosclerosis
As we know LDL has a longer half life then its counterparts
Increased risk at oxidative stress therefore becoming oxidised
And can get into damaged parts of the arterial wall
If oxidised its recognised and engulfed my macrophages
Lipid laden macrophages are called foam cells, which accumulate in the intima of blood vessels to form a fatty streak
This fatty streaks evolves into a ATS plaque
This plaque can then grow and encroach on the lumen of the artery
Too much of this and it can rupture
Which triggers acute thrombosis by platelets clotting the area
This can lead to a stroke if it occurs in the brain or an MI if its in the coronary arteries
Treatment of hyperlipoproteinaemias
First approach
Diet - Reduce cholesterol and saturated lipids in diet.
Increase fibre intake as it reduces the absorption of cholesterol into your blood stream
Lifestyle - Increase exercise, Stop smoking (as its a prime source of oxidative stress, therefore increase chance of cholesterol migrating into tunica intima due to gaps in cells) to reduce cardiovascular risk
If no response - use drugs -
Statins - reduce cholesterol synthesis by inhibiting HMG-CoA reductase e.g. Atorvastatin, therefore prevent the overall production of HMG-CoA to cholesterols
Bile salt sequestrants - Bind bile salts in GI tract, therefore they cant be reabosrbed back into the body, therefore it forces the liver to produce more bile acids using more cholesterol e.g. Colestipol
Cholesterol test
Total Cholesterol (TC) - Ideally 5 mmol/L or less
Non HDL-Cholesterol (total cholesterol minus HDL-cholesterol) - Ideally 4mmol/L or less
LDL-Cholesterol (LDL-C) - Ideally 3 mmol/L or less
HDL-Cholesterol (HDL-C) - Ideally over 1mmol/L (men) and over 1.2mmol/L (women).
Total cholesterol:HDL-C ratio - Ratio above 6 considered high risk - the lower the ratio the better.
Triglyceride (TG) Ideally < 2mmol/L in fasted sample
Inclisiran - inhibits PCSK9 (associated with LDL particle receptor, so when LDL R and LDL is taken into the hepatocyte, instead of recycling the LDL R, the LDL R is broken down with the LDL, so less R on the surface so more LDL in the blood) by inhibiting this, more LDL will be uptaken by cells
