Post-absorption Processing of Lipids Flashcards
Other than production of energy, what is another key role of fats?
They are incorporated into cell membranes
This is particularly phospholipids and cholesterol
What are the essential fatty acids?
What are they precursors for?
Omega-3 and omega-6
They are precursors for eicosanoids
What are eicosanoids?
A family of oxygenated derivatives of 20-carbon polyunsaturated fatty acids
They are signalling molecules
Including prostaglandins, leukotrienes and thromboxanes
What is cholesterol used for?
- cell membranes
- synthesis of bile salts
- synthesis of steroid hormones
- production of Vitamin D
What is the pathway leading from linoleic acid (omega-6) to arachidonic acid?
- linoleic acid (omega-6)
- gamma-linoleic acid (GLA)
- dihomo-gamma-lineolic acid (DGLA)
- arachidonic acid
What is produced from DGLA?
1-series prostaglandins and thromboxanes
What is produced from arachidonic acid?
How is this influenced by aspirin?
- 2-series prostaglandins and thromboxanes
- 4-series leucotrienes
- lipoxins
Aspirin increases lipoxin production
It decreases prostaglandin and thromboxane production
What is produced from DHA/EPA (omega-3)?
How is this influenced by aspirin?
- 3-series prostaglandins and thromboxanes
- protectins and resolvins
- 5-seies leucotrienes
Aspirin increases production of protectins and resolvins
What is linoleic acid?
It is an example of an omega-6 fatty acid
What is the role of lipoxins, resolvins and protectins?
They can orchestrate a resolution to inflammation
What is a chylomicron?
A small fat globule composed of protein and lipid
Where are chylomicrons found?
What is their role?
They are found in the blood and lymph
They transport fat from the intestine, to the liver and adipose tissue
Where are chylomicrons formed?
They are formed in the endoplasmic reticulum of the enterocytes of the small intestine
From here, they supply tissues with fat absorbed from the diet
How do chylomicrons enter the circulation?
They DO NOT pass directly from the GI tract to the liver
They are released into the lymph and enter circulation via the thoracic duct, into the subclavian vein
What happens once the chylomicron has reached adipose, cardiac or skeletal muscle tissue?
Its triglyceride components are hydrolysed by lipoprotein lipase
This leads to the release of free fatty acids which can be absorbed by the tissues
What are the components of a chylomicron?
Triglycerides are within a ball of phospholipids
There are apolipoproteins embedded in the wall
What happens to chylomicron remnants after lipoprotein lipase has taken action?
They travel to the liver for cholesterol synthesis
How is the liver involved in the regulation of cholesterol levels in the body?
- It can synthesise cholesterol for export to other cells
- it can remove cholesterol from the body by converting it to bile salts
It then enters the bile to be eliminated through faeces
What does the liver synthesise for cholesterol transport?
The liver synthesises the various lipoproteins involved in transporting cholesterol and other lipids throughout the body
What is meant by cholesterol synthesis being under negative feedback regulation?
Increased cholesterol in a hepatocyte leads to decreased activity of HMG-CoA reductase
What is contained within a lipoprotein?
- triacylglycerol
- cholesterol
- phospholipids
- apolipoproteins (amphipathic proteins)
How are lipoproteins differentiated?
Based on their density and the types of apolipoprotein they contain
The lower the density of a lipoprotein, the more lipid it contains relative to protein
What are the 4 major types of lipoprotein?
- chylomicrons
- very low-density lipoprotein (VLDL)
- low-density lipoprotein (LDL)
- high-density lipoprotein (HDL)
What is the role of chylomicrons and VLDL?
They deliver triacylglycerols to the cells in the body
Where is VLDL synthesised?
In the liver
What removes the triacylglycerols from the chylomicrons/VLDL?
What does it do to them?
Lipoprotein lipase
It digests the triacylglycerols into fatty acids and monoglycerides
These can diffuse into the cell to be oxidised
They can be resynthesised into triacylglycerols in adipose cells
What is the role of LDL?
It delivers cholesterol to cells in the body
How is LDL formed?
As VLDL particles are stripped of triacylglycerols, they become more dense
They are remodelled in the liver and transformed into LDL
How do cells take up cholesterol via LDL?
Receptor-mediated endocytosis
LDL binds to a specific LDL receptor and it is then internalised in an endocytic vesicle
How is cholesterol prepared for use in the cell after receptor-mediated endocytosis?
Receptors are recycled to the cell surface whilst hydrolysis in an endolysosome releases cholesterol for use in the cell
What is the role of HDL?
It is involved in reverse cholesterol transport
How is excess cholesterol eliminated from the body?
Excess cholesterol is eliminated from the body via the liver
The liver secretes cholesterol in bile or converts it to bile salts
How does the liver remove LDL from the circulation?
The liver removes LDL and other lipoproteins from circulation by receptor mediated endocytosis
What is involved in reverse cholesterol transport?
Excess cholesterol from cells is returned to the liver by HDL
How is HDL synthesised and secreted?
What happens before it returns to the liver?
The HDL precursor is synthesised and secreted by the liver and small intestine
It travels in the circulation and gathers cholesterol to form mature HDL
Mature HDL returns to the liver
By which 2 ways may fatty acids arrive at the peripheral tissue?
- in chylomicrons or VLDL
2. from adipose tissue
How are fatty acids released to peripheral tissues if they are carried by chylomicrons/VLDL?
They are released by lipoprotein lipase
How may fatty acids arrive at the peripheral tissues from adipose tissue?
How are the fatty acids transported?
- triacylglycerols are broken down by hormone sensitive lipase
- fatty acids are released into the blood
- fatty acids are transported to tissues bound to albumin
Why can fatty acids not be used by brain tissue?
Fatty acids cannot cross the blood-brain barrier
What is the first step in the oxidation of fatty acids?
Fatty acids are activated to fatty acyl CoA
This occurs in the cytosol
What is the second step in the oxidation of fatty acids?
B-oxidation which takes place in the mitochondria
What is meant by B-oxidation?
The process by which fatty acid molecules are broken down to generate acetyl-CoA
This can then enter the Krebs cycle
What do long chain fatty acids require for transport?
Carnitine transports long-chain fatty acids (>12 C) across the IMM
What are the 4 stages involved in the carnitine transport system?
- fatty acyl CoA is released from CoA, attached to carnitine - occurs on OMM
- fatty acyl carnitine is transferred across IMM by carnitine acylcarnitine translocate
- fatty acyl carnitine is transported in exchange for free carnitine
- fatty acyl group is transferred back to CoA
What will inhibit the carnitine transport system?
Why is this important?
Malonyl CoA
This prevents synthesis and degradation of fatty acids at the same time
For each turn of the B-oxidation spiral, how many acetyl CoA molecules are released?
What is produced?
What happens to these molecules?
Each turn releases 1 acetyl CoA and produces NADH and FADH2
NADH and FADH2 are oxidised by the electron transport chain
Acetyl CoA enters the Krebs cycle
How many molecules of ATP are produced during B-oxidation of fatty acids?
The overall reaction produces 108 ATP molecules from each molecule of palmitoyl CoA
What controls the process of B-oxidation?
The access of fatty acids to the mitochondria
This is controlled by the concentration of malonyl CoA
How is malonyl CoA formed?
It is formed by acetyl CoA carboxylase during the first step of fatty acid synthesis
What will high concentrations of malonyl CoA inhibit?
Why is this important?
High concentrations of malonyl CoA inhibit carnitine acyl-transferase-1
This ensures fatty acid breakdown is inhibited when energy is plentiful
When are ketone bodies formed and why?
Ketone bodies are formed from excess acetyl CoA
They act as an alternative source of energy to glucose
Where will ketone synthesis occur?
In the mitochondria of liver cells and under conditions where the body relies on fatty acid oxidation for energy
e.g. fasting, uncontrolled diabetes
What happens to ketone bodies after they are formed?
They are released into the blood
They are oxidised to produce energy in peripheral tissues - including brain tissue
What are the 2 main ketone bodies produced by the body?
3-hydroxybutyrate and acetoacetate
What is ketogenesis?
The process of forming ketone bodies in the liver
What is the first stage in ketogenesis, involving acetyl CoA?
Condensation of 2 molecules of acetyl CoA to form acetoacetyl CoA
This is catalysed by 3-ketothiolase
What happens once acetoacetyl CoA is formed?
A condensation reaction occurs between acetoacetyl CoA, acetyl CoA and water
This forms HMG CoA
What happens once HMG CoA is formed?
HMG CoA is cleaved to acetyl CoA and acetoacetate by HMG CoA lysase
How is 3-hydroxybutyrate formed from acetoacetate?
It is formed from the reaction of acetoacetate in the matrix
The equilibrium of the reaction is determined by the ratio of NADH:NAD+
If NADH predominates, 2-hydroxybutryrate forms preferentially
When does ketoacidosis occur?
When the body produces high levels of ketones, which are blood acids
This can be life-threatening
What other compound can be produced from acetoacetate?
Acetone
Where does cholesterol synthesis occur?
In almost all tissues, but mainly in the liver and intestine
How is cholesterol taken up from LDL?
Receptor-mediated endocytosis
LDL binds to receptors on the cell surface and is endocytosed
The cholesterol is released and the receptors are recycled
How does the cholesterol level of the cell determine the amount of cholesterol that is taken up?
LDL receptor synthesis is controlled by the level of cholesterol in the cell
Lack of receptors prevents LDL uptake
What are the 4 stages of cholesterol biosynthesis?
- acetyl CoA is converted to mevalonate (C6)
- mevalonate is converted to phosphorylated isoprene units (C5)
- 6 isoprene units are polymerised to form a 30-carbon chain - squalene
- squalene undergoes cyclisation to form a ring structure - lanosterol - and then cholesterol
What is the most important step in cholesterol biosynthesis?
Where does this occur?
The first step is the most important as it controls rate of synthesis
This process occurs in the cytosol and smooth ER
What mechanism controls cholesterol synthesis?
Cholesterol synthesis is controlled by adjusting the activity or amount of HMG CoA reductase
What 2 factors influence cholesterol synthesis?
- cholesterol levels - high levels will inhibit further synthesis
- energy levels - insulin increases synthesis as it signals energy availability
glucagon inhibits synthesis
How is the activity of HMG CoA reductase controlled?
Through phosphorylation
It is inactivated when energy levels are low
This is controlled by insulin and glucagon
How can cholesterol synthesis be controlled on a nuclear level?
Control of mRNA synthesis allows for the control of transcription of HMG CoA reductase
This is inhibited by high cholesterol and stimulated by insulin
How is rate of degradation of HMG CoA reductase influenced by cholesterol levels?
Rate of degradation of HMG CoA reductase is increased in high cholesterol
What is sterol regulatory element (SRE)?
It is a transcription factor that markedly inhibits gene expression in the presence of sterols
What is SREBP? What does it bind to?
Sterol regulatory binding protein
It binds to the SRE DNA sequence
Where are SREBPs synthesised?
What do they form a complex with?
They are synthesised as precursor proteins in the ER
They form a complex with SCAP
(SREBP cleavage-activating protein)
What is significant about the SCAP molecule?
What happens in high levels of cellular sterols?
It contains a sterol sensory domain
In high levels of cellular sterols, SCAP confines SREBP to the endoplasmic reticulum
What is the action of SCAP when cellular sterol levels are low?
SCAP escorts SREBP to activation in the Golgi
It undergoes 2 proteolytic cleavages to release nuclear SREBP (active TF)
What happens once nuclear SREBP has been formed?
nSREBP translocates to the nucleus and binds to SREs to activate transcription of these genes
This leads to HMG CoA reductase formation
How are cholesterol levels in the body balanced?
They are controlled by a balance between intake, use and excretion
How is cholesterol excreted from the body?
It can only be excreted in faeces as cholesterol cannot be broken down by the body
What are 4 common diseases which are linked to raised cholesterol levels?
- coronary heart disease
- stroke
- Alzheimer’s disease
- steatohepatitis
What is steatohepatitis and what can it lead to?
It is a type of fatty liver disease characterised by inflammation of the liver with concurrent fat accumulation
It leads to cirrhosis and hepatic carcinoma
What are the UK total cholesterol targets?
5 mM or less for healthy adults
4 mM or less for those with other risk factors
How can saturated and trans fats affect the levels of cholesterol in the blood?
Saturated fats raise the levels of LDL cholesterol
Trans fats can raise LDL cholesterol and lower HDL
What factors tend to increase LDL levels?
What can this increase the risk of?
Increased dietary intake of saturated fats (and cholesterol) causes LDL levels to rise
High LDL levels increase the risk of atherosclerosis
What does familial hypercholesterolaemia involve?
A lack of LDL receptors
There is more LDL circulating in the blood as it cannot be taken up
Increased risk of coronary heart disease
What is HDL involved in?
What can high levels of HDL lead to?
Reverse cholesterol transport from the peripheral cells to the liver
High levels of HDL reduce the risk of atherosclerosis
What is Tangier disease?
A lack of HDL
This means sufferers are at an increased risk of coronary disease
How are foam cells formed?
- damage to endothelial cells allows LDL to access the subintimal space
- LDL is oxidised and then internalised by macrophages
- This produces foam cells
What happens to foam cells that leads to formation of an atherosclerotic plaque?
accumulation of foam cells leads to a bulge in the vessel wall - this is an atherosclerotic plaque
a fibrous collagen cap then forms on the plaque
