Lipid synthesis and degradation Flashcards
What are lipids? What are the different lipids?
They are macromolecules soluble in non-polar solvents Fatty acids Glycolipids Glycerophospholipids Sphingolipids Triglycerides Cholesterol
Why is fat such an important store of energy?
Fats are synthesised and stored when our calorific intake exceeds the immediate needs of the body
The energy content of fat per gram is over twice that of either carbohydrate or protein
1g fat- 37kjoules
1g protein- 17kjoules
1g carbohydrate- 16 kjoules
What are the health implications associated with lipids?
40% of the energy of the British Diet is from fat
Obesity among adults rose from 14.9% to 25.6% between 1993 and 2014 in England.
A BMI of 30kg/m^2 classified obese
30,000 premature deaths every year
£4,2bn in 2007 and increased to 6.3bn in 2015
75% of the population will be obese within 15 years
Government policy is to reduce this to <35%
How are fats made and stored?
Fats are most often made from dietary carbohydrates
However some amino acids can also be used
Not all fats are stored as they are also the preferred energy source for cardiac muscle
Fats are stored in the adipose tissues as triglycerides but the majority are synthesised in the liver
Triglycerides are formed from glycerol and 3 fatty acids
Fatty acids:
Chains of methyl groups
Terminal carboxyl group
Double bonds if present are usually in cis conformation
Humans unable to create double bonds less than position 9
Essential fatty acids obtained from the diet
How are lipids synthesised essentially?
Synthesised in the liver from excess glucose
Glucose enters the cell and is phosphorylated to glucose-6-phosphate
In the liver this is performed by the enzyme glucokinase
The G-6-P is then further metabolised in glycolysis to form pyruvate
The pyruvate will then be converted to Acetyl-CoA and react with oxaloacetic acid to form Citrate
This is essentially the tricarboxylic acid cycle
When the levels of ATP are high and the need for glucose is low then the excess citrate is then transported out of the mitochondria where it is converted back to Acetyl-CoA
This is synthesised into fatty acids
The fatty acids will either be retained in the liver as liver lipids but the majority will be transported in the blood as either lipoproteins or free fatty acids bound to albumin and transported to non-hepatic tissues such as adipocytes for storage
Alternatively, the Acetyl-CoA can be used to synthesise cholesterol which, again, is transported arounf the body to non-hepatic tissue
How does the citrate-malate antiporter work?
Transfer of acetyl CoA to the cytosol from the mitochondria requires a specific transport system
This is the citrate-malate antiporter
Acetyl CoA reacts with oxaloacetic acid to give us citrate
The citrate is then transported out of the mitochondria into the cytosol where the Acetyl CoA is regenerated along with the oxaloacetic acid
Oxaloacetic acid is then converted to malate
Malate is then converted to pyruvate, forming NADPH in the process
The pyruvate is then transported back into the mitochondria where it is converted back into oxaloacetic acid and the cycle can repeat
The NADPH is a vital component for the synthesis of fatty acids however additional NADPH can also be provided
What is the first step of fatty acid synthesis?
First step
Acetyl-CoA carboxylase
Acetyl-CoA + ATP + HCO-3 —-> malonyl-CoA + ADP + Pi
C2 C3
Important irreversible regulatory step, activated by citrate (positive feed forward) and inhibited by palmitic acid (negative feedback)
This requires the vitamin biotin
What is the second step of fatty acid synthesis?
Reaction with ACP - acyl carrier protein
Step 2 elongation
Cytosolic
Addition of 2 carbons
1.Acetyl CoA (2C) combines with carbonate to form Malonyl-CoA
2.The malonyl CoA reacts with an acyl carrier protein to form Malonyl-ACP (3C)
This activates the malonyl CoA so that it can undergo further reactions
3.That reaction is with a second molecule of acetyl CoA that has reacted with an acyl carrier protein
This reaction is a condensation reaction which leads to the loss of carbon dioxide and the formation of Acetoacetyl-ACP (C4)
4.Then there’s a sequence of reactions; a reduction, dehydration and another reduction this will for a Butyryl-ACP (4C)
5.This molecule will react with another Acetyl-CoA molecule that has undergone the same process previously to form Malonyl-ACP (3C)
6.These two combine to produce CO2 and the resulting 6 carbon molecule
The process requires the use of NADPH
What is fatty acid synthase and how does it work?
The protein responsible for fatty acid synthesis is called fatty acid synthase
This is a multienzyme complex that brings together the substrate and the enzyme active site
Intermediates are covalently linked to acyl carrier protein (ACP)
This enables the efficient and rapid movement of the growing fatty acid chain to be passed from one active site to the next
The efficiency of the reaction is further enhanced as the enzyme exists as a dimer arranged head to tail
What is cholesterol like?
Rigid hydrophobic molecule virtually insoluble in eater
Precursor of sterols, steroid and bile salts
Important membrane components
Transported in the circulation as the cholesteryl esters
Cannot be used to provide energy
Cholesterol imbalance can lead to significant health issues
What is cholesterol synthesis like?
Cholesterol is synthesised mostly in the ER
Over 30 steps are involved
Starts with the activation of acetate, acetyl-CoA
Major regulatory step is the conversion of 3-hydroxyl-3-methylglutaryl CoA (HMGCoA) to mevalonate
Cholesterol inhibits HMGCoA reductase, the enzyme involved in its own synthesis
Difficult to reduce circulating cholesterol by diet alone as endogenous synthesis is increased
What are the three main stages of fatty acid degradation?
Release of energy from reserves stored in adipose tissue requires three steps
Step 1: mobilisation-adipocyte
Step 2: activation-liver cytosol
Step 3: degradation-liver mitochondria
What happens in the fatty acid mobilisation stage?
Hormones that stimulate the mobilisation of fatty acids are glucagon and adrenalin
These act through several transmembrane domain receptors, resulting in an increase in cyclic AMP
Cyclic AMP will then activate Protein kinase A
Protein kinase A will then phosphorylate and activate Triacylglycerol lipase
This triacylglycerol lipase will then break down triglycerides into diacylglycerol
Following the activity of lipases is the release of glycerol and further free fatty acids which are then transported back to the liver
What happens in the activation stage of fatty acid degradation?
Long chain FA activated on the OMM to form acyl-CoA
Transported to inner mitochondrial matric for oxidation using carnitine
Carnitine deficiency can cause muscle weakness or even death
Transport is inhibited by malonyl-CoA
So the carnitine reacts with the acyl-CoA to give acyl carnitine
This is then transported across the inner mitochondrial membrane by a translocase and the acyl carnitine is then broken down to give us carnitine and a acyl CoA again
What happens during the degradation stage of fatty acid degradation?
Fatty acid oxidation (b-oxidation)- liver mitochondria
Acyl-CoA degraded by sequential removal of two carbon units
As a result FADH2, NADH and acetyl-CoA are produced
FADH2, NADH form ATP
In the liver Acetyl-CoA does not enter citric acid cycle
In non-hepatic tissue complete oxidation of palmitate yields 106 molecules of ATP
Odd chain length yield propionyl-CoA in the last round of oxidation
Propionyl-CoA is converted to oxaloacetate and used for gluconeogenesis
Odd numbered double bonds are removed by isomerase and even double bonds by reductase and then isomerase
Thiolysis is a splitting of the molecule
This process will continue until the fatty acid chain has been completely broken down
