Lipid synthesis and transport in the blood Flashcards
Definition of plaque
Complex structure involving inflammation and proliferation of smooth muscle in artery wall. Contains connective tissue and pool of cholesterol
Definition of foam cells
Macrophages filled with lipid, mainly cholesterol
Describe the use of lipids as a store of fuel
How is excess carbohydrate stored in the long term
Energy providing food consumed in quantities greater than needed at the time
Fuel stored
Carbohydrate stored as glycogen, limited store
Long term reserve is lipid as TAGs
What happens when glycogen storage is full
Glucose converted to TAGs in the adipose tissue
How are fatty acids synthesized
Formation of malonyl CoA from Acetyl CoA
What does malonyl CoA inhibit
Enzyme stimulated by insulin in fed state in the cytosol
Normally, acetyl CoA not found in the cytosol.
- Acetyl CoA + Oxaloacetate =(citrate synthase)=> Citrate =(moves into cytosol=>
- Citrate =(ATP citrate lyase)=> Acetyl CoA + Oxaloacetate
-Acetyl CoA + ATP + CO2 =(Acetyl CoA carboxylase)=> Malonyl CoA + ADP + Pi (rate limiting step)
Malonyl CoA signifies fed state
Malonyl CoA inhibits carnitine transferase
How are fatty acids synthesized
Elongation of carbon chain
Acetyl CoA + CO2 =(fatty acid synthase + NADPH)=> Malonyl CoA
Malonyl CoA + Acetyl CoA =(fatty acid synthase + NADPH)=> 4 carbon chain + CO2
4 carbon chain + Malonyl CoA =(fatty acid synthase + NADPH)=> 6 carbon chain + CO2
Why is fatty acid synthase special
Made up of many enzymes and a large AS
Hydrogenate then dehydrate
How is TAG synthesised
What is it synthesised from in glycolysis
How are TAGs then processed to form lipoproteins
In the liver
- Dihydroxyacetone phosphate => glycerol phosphate
- Glycerol phosphate + 3 FA => TAG + Pi
TAG + other lipids + apoproteins = TAG,Apoprotein,Phospholipid,Cholesterol
Why are apoproteins bound to TAG
Apoproteins don’t function on their own
Describe the structure of a lipoprotein
What 2 structures are found in the inner core
What 3 structures are found in the membrane
Inner core
-TAGS
-Cholesterol esters (can’t form membranes)
Outer shell
- Single phospholipid layer
- Cholesterol (unesterified)
- Apoproteins (hold structure together, activate enzymes, recognition of other cells)
2 main properties of lipoproteins
Lipids insoluble in water
Needs to be transported as a lipid protein complex
3 main properties of apoproteins
Structural role
Recognized by receptors
Activate certain enzymes in lipid metabolism
4 classes of lipoproteins and their properties
Chylomicrons
-Largest, lowest density, carry mainly dietary TAG
Very low density lipoprotein (VLDL)
-Carries mainly endogenous TAG
Low density lipoprotein (LDL)
-Carries mainly cholesterol to the tissues
High density lipoprotein (HDL)
-Carries mainly cholesterol from tissues to the liver
Transport of exogenous fat
Nascent chylomicron (TAG, CE, C, apoB48) from small intestine Nascent chylomicron joins to apoC2, apoE (from HDL) to form a chylomicron
Lipoprotein lipase (LPL, insulin activated) in the capillary endothelium hydrolyses the chylomicron into FFA, glycerol, (TAG, CE, C, apoB48, apo E as 1 unit) ApoC2 returns to HDL
FFA rebuilt up to form TAG in adipose
TAG, CE, C, apoB48, apo E, (remnant chylomicron) binds to apoE receptor on liver where it is broken down
Glycerol also enters the liver
Transport of endogenous fat
TAG, CE, C, apoB100 (VLDL) unit leaves liver and binds with apoC2, apoE (VLDL)
VLDL transported in the capillaries to LPL where it is broken down into FFA into the tissue, glycerol to the liver and the remainder forms IDL
IDL (CE, C, TAG, apoC, apoE, apoB100) splits so apoB100 and CE, C, TAG form LDL. Remaining apoE and apoC2 returned to HDL
. 50% of these LDLs enters peripheral tissue via B receptors, the other 50% enters the liver and is broken down
ApoC, ApoE returns to HDL which can be transferred to VLDLs
Role of HDL in lipid transport
HDL generated by liver and small intestine as cholesterol free lipoproteins and apoA1.
LCAT (lecithin cholesterol acyl transferase), activated by apoA1, takes C from peripheral tissues and converts it into CE by adding 1 FA from PC. CE is sequestered into HDL core. PC becomes LPC
When HDL is full, inhibits LCAT. CETP used to transfer some CE to VLDLs so HDL can continue to remove C from cells
SR-B1, HDL receptor so cholesterol esters can be used in the liver
Describe the receptor mediated endocytosis of LDL
LDL binds to receptors on cell surface and are taken up by endocytosis.
The receptors are recycled and are ready to receive more LDL from the cell surface
Lysosomes of LDL are formed
Enzymes of cholesterol synthesis (HMG CoA) lead to cholesterol synthesis from LDL
Cholesterol controls its own synthesis and the no of LDL receptors on the cell surface by controlling the amount of translation for the receptors
How is cholesterol synthesised
Acetyl CoA + Acetoacetyl CoA
HMG CoA =(HMG CoA reductase)=> Mevalonate
Cholesterol
How is cholesterol synthesis controlled
If we consume cholesterol, cholesterol synthesis is inhibited
LDL receptors and the effects of LDL receptor deficiency
Recognize B100
Remove LDL from the circulation
Receptor mediated =endocytosis
Deficiency of LDL receptors (familial hypercholesterolemia)
V high blood cholesterol levels
Premature death from atherosclerosis
Hyperlipidaemias
What are the 2 types
Hypercholesterolemia
Hypertriglyceridaemia
Has a genetic/environmental element
What are the 4 types of genetic hyperlipoproteinaemias
Defective LDL receptor
Lipoprotein lipase deficiency
Deficiency of apoC2
Deficiency of apoproteins involved in remnant uptake
What can happen if there is a defective LDL receptor
Hypercholesteralaemia
Increases LDL in blood
What can happen if there’s a lipoprotein lipase deficiency / apoC2 deficiency
Increase chylomicrons and VLDL
What can happen if there’s a deficiency of apoproteins involved in remnant uptake
Increase in chylomicrons and VLDL remnants
Risk factors for secondary hyperlipoproteinaemias
Obesity Diabetes mellitus T2 Dietary FA SFA vs PUFA omega 6 PUFA, lower cholesterol omega 3 lower TAG Alcohol
Lipoprotein a
What is it
What pathologies is it associated with
In high conc associated with increased CHD risk
LDL + apoa
Levels are genetic, can be increased by trans fat, decreased by estrogen
Slows breakdown of blood clot by competing with plasminogen
Relationship between average serum cholesterol and mortality for CHD
Increased serum cholesterol, increased mortality for CHD
Relationship between average HDL cholesterol and mortality for CHD
Increased HDL cholesterol,
Decreased mortality for CHD
Describe atherosclerosis
Complex structure involving inflammation and proliferation of smooth muscle in artery wall
Contains connective tissue and a pool of cholesterol rich lipid
Starts as fatty streak from accumulation of foam cells
Foam cells absorb LDL
Foam cells=macrophages, lipid filled, mainly cholesterol
Describe normal LDL metabolism
Cholesterol synthesis in the liver
Cholesterol released into the blood as VLDL
LPL results in FFA absorption into peripheral tissues, glycerol to liver and remnants as IDL
HL (hepatic lipase) hydrolyses TAGs in IDL to form LDL
50% of LDL goes to extra hepatic cells via B receptors
50% of LDL goes to the liver to be broken down again
No LDL enters the macrophages
What happens when the LDL is modified and oxidized?
Not recognized by normal B100 receptors, taken up by scavenger receptors in foam cells
Receptors not down regulated, results in accumulation of cholesterol in foam cells
Instead of LDL entering the liver for breakdown, it all enters the macrophages
