Lipid Transport Flashcards
Where are Lipids are transported from and to where?
- The gut to the liver
- Liver to non-hepatic tissue including adipocytes
Non-hepatic tissue back to the liver
Fat and lipids in the circulation composition
What do the percentages greatly depend on?
What is special about the fat and lipids in circulation?
- Triagylcerols (45%)
- Cholesterol esters cholesterol (15%)
- Phospholipids (35%)
- Free Fatty acids(5%)
Percentage greatly depends on diet
All these in circulation are insoluble in water
What are free fatty acids formed from?
Formed from triglycerides stored in adipose tissue
How do free fatty acids circulate and what are they bound to?
Circulates bound to protein as Na+ salt particularly albumin
What does unbound FA act as?
Act as a detergent
What are fatty acid saturated at about?
2mM
How do fatty acids enter cells?
Enter by simple diffusion
What is the intracellular concentration of FFA kept at?
Intracellular concentration of FFA kept low
What are lipoproteins carried as in blood?
Carried in the blood as plasma lipoproteins
What are the 5 types of lipoproteins?
○ Chylomicrons ○ VLDL ○ IDL ○ LDL HDL
How are lipoproteins characterised?
They are characterised by how they behave under density centrifugation
What does each lipoprotein have?
Each lipoprotein has a different function
In the structure of a lipoprotein, what protein is present?
Contains at least one very large protein called Apolipoprotein
What else is present in the structure of a lipoprotein?
Phospholipids and cholesterol also present
What is the content of lipoproteins largely?
Content is largely the phospholipids the triglycerides and cholesterol esters
What are phospholipids on what is considered the membrane?
Single layer of molecule
What determines the density of the lipoproteins?
• Largely the protein and triglycerides that determine the density of the lipoproteins
○ The more triglycerides the less dense
What do different lipoproteins have?
Different lipoproteins have different apoproteins/apolipoprotein
What can different lipoproteins interact with?
Different lipoproteins can interact with each other and exchange apoproteins
What are one of the largest synthesised in the body?
Apoproteins are one of the largest proteins synthesised in the body
What are the functions of apoproteins?
• Structural-backbone of lipoproteins
Solubilise lipids-allow lipids to be soluble in aqueous environment
What do lipoproteins act as?
Act as enzymes or enzyme cofactorsAct as enzymes or enzyme cofactors
What does Apo C2 activate?
Activates lipoprotein lipases
What is Apo A1?
Apo A1 is a cofactor for lecithin cholesterolacyltransferase
What targeting are apoproteins used for?
Tissue targeting
What do Apo B100 and Apo E bind to
Apo B100 and Apo E bind to LDL receptor
What else does Apo E bind to?
Apo E also binds to LDL receptors
What are chylomicrons formed by?
Formed by cells that line the gut
Steps of the formation of chylomicrons
• In the lumen, triglycerides broken down to free fatty acids and monoacylglycerols under the influence of lipases
• Taken into cell and reform into triglycerides
These will join with apolipoproteins to from chylomicrons
Once Chylomicrons are formed, what happens?
Chylomicrons secreted into lymphatic system
Once in the lymphatic system, they’re carried to the superior vena cave via thoracic duct meaning it goes directly into circulation
What happens if chylomicrons are secreted into the veins?
- If secreted into veins, it’ll be metabolised in the liver
* This ensures lipids are available to the extrahepatic tissue
Due to what reason do chylomicrons have a low density?
Low density due to high Triglyceride
What is the majority protein when chylomicrons are first formed?
Majority protein is ApoB48 when first formed
What does nascent chylomicrons interact with when in circulation?
Forms nascent chlyomicron and interacts with HDLs when in circulation
What will ApoB48 be exchanged with to form what?
They’ll be exchanged with other apoproteins primarily ApoC2 and APoE forming mature chylomicron.
What do chylomicrons reflect?
Reflect meal composition
What vitamins do chylomicrons contain?
Contain fat-soluble vitamins(A and E)
Lifetime of chylomicrons compared to triglycerides in circulation?
1 hour for chylomicrons
5 minutes for triglycerides
Km of Lipoprotein lipase in adipocytes compared to muscles and what does that mean
Km of LPL in adipocytes is greater then Km in muscle
Meaning more saturated at much higher concentrations of circulating lipoproteins than it will be in the muscle
Muscle fully saturated at low levels so the muscle will be able to use the circulating lipoproteins at low concentration
What are LDL’s on adipocytes stimulated by?
LPL on adipocytes are stimulated by insulin
What is Type 1 Hyperlipidaemia caused by and its characteristic?
Type 1: Deficiency in LPL or ApoC2-characterised by high plasma triglyceride
What is Type 2 hyperlipidaemia caused by and its characteristics?
most are caused by a genetic defect in the synthesis, processing or function of the LDL receptor
Characterised by high LDL
What causes type 4 hyperlipidaemia and what does it result in?
due to obesity or alcohol abuse
Most common form results raised VLDL concentrations
Where is VLDL synthesised?
Synthesised in liver ER and modified in golgi
What is the predominant apoprotein in VLDL
Predominant apoprotein is B100
What are the similarities and differences between B100 and B48 apoprotein?
Predominant apoprotein is B100-made from the same gene as B48- only difference is that B100 is 100% of the gene whereas B48 is only 48% of the gene
What do VLDL acquire from HDL?
Acquire Apo E and C from HDL
What are VLDL’s responsible for transporting?
Responsible for transporting endogenously synthesised lipids
What are VLDL metabolised by as they circulate?
Metabolised by LPL’s as they circulate
What enhances the formation of VLDL?
○ Dietary carbohydrate
○ Circulating FFA
○ Alcohol
Raised Insulin and decreased glucagon
What removes the remnants and what is it removed by?
Remnant removed by the liver by apoE
What is one fate of VLDL?
One fate is when majority of triglycerides are lost, it returns to the liver
What is another fate of VLDL and where does it take place?
○ Other fate is of VLDL’s that they form intermediate density lipoproteins
Takes place on the hepatic sinusoids
What are LDL’s the major carrier of?
Major carrier of cholesterol
How long does it take to metabolise LDL’s?
Takes up to 3 days
Where does LDL carry cholesterol to regulate what?
Carry cholesterol to the periphery and regulate de novo synthesis
What apolipoprotein do LDL contain and what do they bind to?
Contain 1 ApoB100 which can bind to a specific receptor on hepatocytes
How are IDL’s formed from VLDL’s?
By lipase
What happens to IDL’s?
Some removed by liver whilst some formed into LDL which are rich in cholesterol
How are the LDL’s formed from IDL’s removed?
60% of LDLs removed by liver and 40% by non hepatic tissue for steroid biosynthesis
What is the cholesterol from LDL’s used for?
Used for hormone production
What are HDL’s?
Circulating reservoir of apoliproteins(C2 and apo e)
Where are the apolipoproteins in HDL’s obtained from?
Apolipoproteins obtained from VLDLs and chylomicrons
What to HDL’s do?
Remove cholesterol from plasma
What enzyme fo HDL’s contain and what do they do?
Contain LCAT enzyme which esterifies cholesterol
Where are HDL’s transported too?
• Transported to liver and steroid producing cells
How does cholesterol transfer occur in HDL’s?
HDL bind to lipoproteins and cells via apo E this is important for cholesterol transfer
What is the fate of cholesterol?
Return cholesterol to liver but also transfer it to VLDLs and LDLs-cholesterol ester transfer protein
What is reverse cholesterol transport?
HDL remove cholesterol present in plasma membrane
What happens in reverse cholesterol transport?
- Endothelial cells express transporter ApoA1 in order to this
- Transporter transfers the cholesterol from the inner surface of membrane to extracellular surface where it interacts with ApoA1 on HDL
Then transported away to cells that need it or to liver.
What is the HDL/LDL normal ratio?
3.5
What happens in receptor mediated endocytosis?
ApoB100 and ApoE bind to LDL receptors on surface of hepatocytes
What are scavenger receptors in receptor mediated endocytosis and where are they expressed?
• ApoB100 and ApoE bind to LDL receptors on surface of hepatocytes
• There are also scavenger receptors which are not regulated meaning they bind lipoproteins only at high concentrations
Expressed on endothelial cells and macrophages
How to LDL’s interact with receptors in liver?
LDL will bind to LDL receptor on hepatocyte
How are receptors on liver concentrated?
Receptors are concentrated in coated pits
What do the pits have which is important?
Pits have clathrin which is important for the uptake of LDL
How are LDL’s transported in hepatocytes to lysosomes?
- Membrane pinches off to form endosome
- Endosome starts to break down receptor which are recycled
- Remaining endosome with LDL will fuse into lysosomes
What happens to the cholesterol esters in lysosomes and why so?
• Cholesterol esters converted into cholesterol and diffuse into cytoplasm where they’re immediately esterified
Free cholesterol in cell is not desirable
How is the whole process of LDL interaction with receptors on liver regulated?
Whole process regulated by intracellular concentration of cholesterol
What does increased cholesterol inhibit in the regulation of the uptake and synthesis of cholesterol?
Increased cholesterol inhibits HMG-CoA reductase activity
What does HMG-CoA reductase do?
Reduces LDL receptor expression
What step is HMG-CoA in the synthesis of cholesterol?
HMG-CoA reductase is the rate limiting step
What do statins inhibit in the regulation of uptake and synthesis of cholesterol?
Statins inhibit HMG-CoA reductase, decreasing cholesterol synthesis
What effect to statins have on the expression of LDL receptors on cell surface and what does this result in?
Will increase in the synthesis of LDL receptor on the cell surface
LDL cholesterol uptake by cells increased and therefore lowering circulating cholesterol
What happens in FH disorder?
Loss of LDL receptor function
What type of disorder is FH?
A recessive disorder
What is there a high level of in FH?
High level of serum cholesterol
What are the symptoms of FH?
○ Develop blocked arteries
Die young from heart attacks
How is de novo synthesis not regulated?
De novo synthesis not regulated by LDL
What causes FH and the effect it has on LDL receptor?
Single amino acid substitution prevents localisation of the LDL receptor to the coated pits
What are the two type of receptors?
High affinity LDL receptors and Low affinity scavenger receptor
Where are the two types of receptors present?
○ Endothelial cells
○ Macrophages
VSMC
When is low affinity scavenger receptor active?
Active when plasma LDL is high
How are lipoproteins regulated hormonally?
Insulin, Cortisol, Thyroid hormones
How are lipoproteins regulated by nutrition?
decreased synthesis during fasting, increased by dietary fats
What hormone effects LDL expression?
Oestrogen
What are the abnormalities involved in lipid transport?
• Diabetes Mellitus: increased FFA mobilisation, decreased Chylomicron and VLDL utilisation
• Gene defects: apolipoproteins, enzymes or receptors.
• Leading to: hypercholesterolemia, atherosclerosis
Obesity: hypertension, NIDDM, hyperlipidaemia and hyperglycaemia
