S2: Lipid Transport Flashcards
List places lipids are transported from
- Gut to the liver
- The liver to non hepatic tissue including adipocytes
- Non-hepatic tissue back to the liver
List the percentage of different types of fats and lipids in circulation
- Triacylglycerol (triglycerides) (45%)
- Cholesterol esters and free cholesterol (15%)
- Phospholipids (35%)
Free fatty acids (5%)
The % given in human plasma varies greatly with nutritional state
Do fats and lipids dissolve in plasma?
All are insoluble in water, they are not transported completely freely dissolved in the blood. This is because they are hydrophobic and also they interfere with membrane structure (being components of membranes themselves)
What are free fatty acids? How are they transported?
- Formed from triacylclycerides broken down into glycerol and free fatty acids
- Stored in adipose tissue
- They are transported bound to albumin as Na+ salt
- Fatty acids enter cells by simple diffusion and intracellular concentration of FFA is kept low
How are the majority of lipids transported in the blood?
They are transported in the blood as plasma lipoprotein. These are relatively large structures consisting of both lipid and large proteins (called apolipoproteins),
What are the 5 types of lipoproteins?
What are they classified by?
- Chylomicrons
- Very low density lipoproteins (VLDL)
- Intermediate density lipoproteins (IDL)
- Low density lipoproteins (LDL)
- High density lipoproteins (HDL)
They are classified by their density.
Chylomicrons have the lease density but are the largest in size. HDL have the highest density.
What is a lipoprotein?
Large protein with phospholipids orientated around the outside (similar to membrane) but in a single layer. The hydrophobic core contains compounds such as cholesterol esters and triglycerides.
Compare lipoprotein composition of chylomicrons and HDL
Chylomicrons have a very low density, they have high TG and low protein.
HDLs have a very high density with low TG and high protein.
List multiple functions of apolipoproteins/apoproteins
- Structural = form a substrate in which lipid can be constructed
- To solubilise lipids= allowing body to transport a difficult class of molecules
- Act as enzymes or enzyme cofactors= Apo C2 helps activate lipoprotein lipase, Apo A1 transfers some lipids between particles
- Allow tissue targeting to specific tissues= Apo B100 and Apo E bind to the LDL receptor, Apo E also binds to the HDL receptor
Explain the course of dietary lipids
Triglycerides we consume are broken down by lipases in the gut to fatty acids and monoacylglycerols
The triglycerides are then assembled into a chylomicron along with other lipids (phospholipids and cholesterol) and proteins. They are low density
due to high TG.
Chylomicrons are then released into the lymphatics which carries them via the thoracic duct to the SVC - secreted by reverse pinocnocytosis. By this pathway dietary fats avoid the direct delivery to the liver and instead made available to extrahepatic tissue (i.e. they have first call). This is very different to digested proteins and carbs which are released into the portal vein and delivered directly to the liver.
Apo C2, C3, E and B48 added in the SER
Explain removal of fatty acid from lipoprotein
Lipoprotein lipase (LPL) is expressed on top of endothelial cells and this is activated by the apolipoprotein Apo C2
When LPL is activated, the TG is broken down and there is diffusion of across the membrane of free fatty acid.
This continues as the chylomicron goes around the circulation and it gains density
Compare the KM of LPL isoform in adipocyte and muscle
Km adipocyte > muscle
What stimulates LPL on endothelial cells and adipocyte?
LPL activated by Apo C2 on endothelial cells
LPL on adipocyte activated by insulin
Name 3 types of hyperlipidaemia (high levels of circulating lipids)
Type 1: Deficiency by lipoprotein lipase or Apo C2 - characterised by high plasma triglycerides
Type 2: Most caused by genetic defect in synthesis processing or function of LDL receptor - characterised by high LDL
Type 4: Often due to obesity or alcohol abuse - most common form results in raised VLDL concentrations
Describe chylomicrons
- Contents reflect meal composition
- Low density due to TAG (triaglycerol)
- Contain fat soluble vitamin A and vitamin E (important for preventing oxidation of lipids)
- Circulate for 1 hr but half life of TAG is only 5 mins so they are rapidly modified by LPL which breaks down TAG causing uptake of fatty acid by tissue
- As chylomicrons go round the circulation, the density of these particles increase as chylomicron remnants (TAG) is removed by the liver. This is done by interaction of Apo E with receptors on hepatocytes
How are chylomicron remnants removed?
How does this affect density?
They are removed by the liver. This is done through interaction of Apo E with receptors on hepatocytes.
This increases density as TAG is removed
What is the main function of chylomicrons?
Transporting exogenous lipids from gut around the circulation ending up in the liver
What is the main function of VLDLs?
Transport lipids derived from the liver around the body
Describe VLDLs
- Synthesised in the liver ER and golgi body
- Released with apolipoprotein B100 and then they acquire Apo E and Apo C2 from HDL. These are then mature VLDL.
- They also interact with endothelial layer and are metabolised by LPL
- TAG with VLDL has a longer half life 15-60mins
- Remnant removed by the liver by apoE
Lipids associated with VLDLs are on a greater distance transport system.
What enhances VLDL formation?
- Dietary carbohydrates (if there is excess, excess is synthesised into lipids usually VLDLs)
- Amount of circulating FFA
- Alcohol - enhances VLDL synthesis hence increasing lipid transport
- Raised insulin and decreased glucagon
Explain how VLDL become mature VLDL
The VLDL is released as a nascent (young) particle and then acquires ApoE and ApoC-2 from HDLs. These then form mature VLDLs.
Explain the process on how IDL and LDL is formed
Mature VLDL circulate through the blood and they are acted upon by LPL and they get smaller.
There are then two pathways to take: go back to liver as VLDL remnants to be removed by ApoE or they can be converted to IDL through removal of more TGs.
IDL can be removed by liver or IDLs are converted to LDLs which occurs in the liver sinusoids
Describe LDLs
include their function
- LDLs are the major carrier of cholesterol
- Long half life
- Carry cholesterol to the periphery and regulate de novo synthesis of cholesterol through Ap B100 acting on receptors on hepatocytes
The LDLs can be taken up by the liver and removed or taken up by non-hepatic tissue through interacting with the LDL receptor.
What apolipoprotein is needed for remnants to be removed in the liver?
Apo E
Describe HDLs
include their function
- HDLs reverse cholesterol transport
- Take up cholesterol from the circulation e.g. plasma or dead and dying cells e.g. mopping up and take cholesterol back to the liver and steroid producing cells
- HDL are made in the liver and intestine by budding from VLDL and chylomicrons from free apoA1
- They are a circulating reservoir of apolipoproteins (C2 and ApoE)
- Contain the enzyme lecthin cholesterol acetyltransferase (LCAT) which esterfies cholesterol
- HDL binds to lipoproteins and cells via ApoE which is important for cholesterol transfer
- They also transfer cholesterol to VLDLs and LDLA via cholesterol ester transfer protein as well as return it to the circulation.
What enzyme esterifies cholesterol?
Lectin Cholesterol Acetyltransferase (LCAT)
HDLs contain this enzyme
How are HDL and LDL used clincially?
HDL as good cholesterol
LDL as bad cholesterol
HDL/LDL ratio is used to assess susceptibility to heart disease and normal individuals have a ratio 3.5
How are lipoproteins removed from the circulation?
Receptor mediated endocytosis.
Lipoproteins act at specific tissues
Explain the uptake of LDLs
- LDLs in the circulation can bind to specific receptors expressed on endothelial cells
- The receptor and LDL is endocytosed
- Vesicle fuses with endosomes which contain enzymes responsible for breakdown of protein and metabolism of lipids
- Receptor detaches and is reinserted into membrane
- There is further fusion of LDl with lysosome which provides hydrolytic enzymes
- The apoliprotein may be broken down to give amino acids, phospholipids give FFA and triglycerides give cholesteryl ester droplets.
How is the uptake of LDL/other lipoproteins regulated
Regulated by amount of cholesterol in cell itself
Increased cholesterol inhibits HMG-CoA reducatase activity which reduces LDL receptor expression
Two main mechanisms by which the cholesterol levels regulate LDL receptor uptake activity
- LDL receptor synthesis and expression on cell surface - elevated cholesterol will signal that more receptors on surface is not required so pathway inhibited
- HMG-CoA reducatase and cholesterol synthesis - as cholesterol increases activity of enzyme decreases
How do statins affect LDL uptake?
- Statins inhibit HMGCoA reducatase
- This decreases cholesterol synthesis (which then increases the synthesis within cells)
- Increase in expression of LDL receptor at the cell surface
- Increase LDL-cholesterol uptake
- Lowers circulating cholesterol
What is Familial Hypercholesterolemia (FH)?
What symptoms do Homozygous individuals have?
Loss of LDL receptor function
- High serum cholesterol
- As a result develop blocked arteries - atherosclerosis
- As a result die young from heart attacks
- De novo synthesis is not regulated by LDL (as cell thinks it has less cholesterol)
What is the genetic cause of LDL receptor function loss in FH?
It is caused only by a small mutation in the receptor, a single AA substitution that prevents the localisation of the LDL receptor to the coated pit
What are the two type of LDL receptors?
High affinity LDL receptor
Low affinity scavenger receptor
What is the high affinity LDL receptors relationship to uptake?
High affinity LDL receptor and relationship to uptake is saturatable whereby if LDL increases beyond ability of LDL receptor, LDLs will build up.
Where is low affinity scavenger receptors found?
- Endothelial cells
- Macrophages
- VSMCs
What is the function of low affinity scavenger receptor?
- Take up LDL from plasma
- These receptors are only active when circulating levels of plasma LDL are very high or when chemically modified
- Not regulated by cholesterol
- The intracellular concentration of cholesterol is ultimately detrimental to the cell, short term low levels can be dealt with but high levels cannot be dealt with and cause problems
How is therapy for treating high cholesterol combined?
Inhibiting de novo synthesis
Inhibit absorption from gut
How are statins competitive inhibitors of HMG-COA reductase?
Vmax same
Km increased
What regulates lipoprotein?
Hormonal regulation: Insulin, cortisol, thyroid hormones
Nutritional status: Decreased synthesis during fasting, increased dietary fats
LDL receptor expression: Oestrogen
Abnormalities of lipid transport
Diabetes Mellitus:
- Increased FFA mobilisation
- Decreased chylomicron and VLDL utilisation
Gene defects:
- Apoproteins, enzymes or receptors leading to hypercholesterolaemia, atherosclerosis
Obesity:
Hypertension, hyperlipidaemia and hyperglycaemia
