CELL Lipid Synthesis and Degradation Flashcards
Fats play an essential role in many biological functions
4 roles?
Fats play an essential role in many biological functions including:
• Membranes
• Important in uptake of fat-soluble vitamins
• Used as precursors for steroid hormones
• As an energy store
Why is Fat is such an important store of energy?
Fat is such an important store of energy because the energy content of fat per gram is over twice that of either carbohydrate or protein. So, fat is a very good way of storing energy.
There are major health implications of fat:
- 40% of the energy of the British Diet is from fat.
- In 2010 62.8% of adults (16+) were overweight or obese. 30.3% of children (2-15) were overweight or obese.
- A massive 26.1% of all adults and 16% of children were obese.
This has huge costs on the NHS and results in many premature deaths every year.
The culprits of these problems are:
- Fatty acids
- Triglycerides or Neutral Fats
- Cholesterol
Fatty Acid Synthesis
when do we store fat?
what used fats as preferred source of energy?
what is msotly used for energy?
where is fat mostly stored? where is it mostly synthesised?
When calorific intake usually in form of carbs exceeds consumption, excess is laid down as fat. This is because we are derived as hunter-gatherers, the body is designed for periods of famine.
- Some tissues such as cardiac muscle use fats as their preferred energy source.
- However, dietary carbohydrate is the most common source, although amino acids can also be used.
- Fats are stored in the adipose tissue as triglycerides but the majority are synthesised in the liver
Lipid Synthesis and Degradation
where does synthesis and degradtion take placr? where does synthesis occur? degradation?
Most of the lipid synthesis and degradation occurs in the liver hepatocytes, with synthesis occurring in the cytosol and the breakdown (through beta oxidation) mostly occurring in the mitochondria.
o These reactions are largely reciprocally regulated, you get synthesis when there is excess calorie intake and during this breakdown is inhibited.
o If you need breakdown then the reactions leading to synthesis are inhibited.
what are triglycerides
structure?
why is the glycerol key?
- Triglycerides are neutral fats, they consist of three fatty acids attached to a glycerol backbone.
- Triglycerides are concentrated stores of energy.
- Remember that the glycerol can be made from glycolysis by glycerol-3-phosphate, glycerol can also be fed into glycolysis at this point.
What are fatty acids?
structure?
saturation?
example of 2 important ones?
what are essential fatty acids?
- Fatty acids are chains of methyl groups with a carboxyl group at the end (terminal).
- The fatty acids can be saturated with single bonds or unsaturated with double bonds.
- An example of two important ones are palmitate and oleate.
- Humans are unable to create double bonds in positions less than position nine, so fatty acids that have these are essential fatty acids and we must obtain them from out diet
Making Fatty Acids
what is the starting block?
what would normally happen in a cell that wanted to make atp this way?
what happens in hepatocyte? what is trnasported out of where? what is this used for?
4 fates of fatty acids in the liver?
where does fatty acid synthesis occur? what 3 things is required and where do they come from?
what is a simple way of lookimf at fatty acid synthesis?
where does the NADPH come from? (2)
The starting block for fatty acid synthesis is Acetyl-CoA.
• If in a cell that wanted to generate ATP, the Acetyl-CoA would feed into the Krebs cycle and react with oxaloacetate to form citrate and go on to result in the ETC.
However, in a hepatocyte this isn’t generally how they make their energy, instead they make fatty acids. The following occurs:
- The citrate made is transported out of the mitochondria and remove the Acetyl-CoA
- The Acetyl-CoA then used to build up fatty acids
- These fatty acids can either remain in the liver (liver lipids) or be exported bound within lipoproteins or bound to albumin as free fatty acids
- Alternatively, the Acetyl-CoA can be used to make cholesterol, cholesterol is then transported to various tissues to be incorporated into membranes or for steroid synthesis
So, fatty acid synthesis occurs in the cytosol and requires:
• Acetyl-CoA
• NADPH (from pentose phosphate pathway)
• ATP
Fatty acid synthesis involves the sequential addition of 2 two-carbon units derived from Acetyl-CoA.
Citrate malate shuttle provides 40% NADPH needed for fatty acid synthesis 60% comes from the pentose phosphate pathway
Transfer of acetyl-CoA to cytosol
why must there be a transfer? from where to where? what is used for this transport?
why is the process cyclical?
how does the transport occur? so what is transported out? what is this broken down into? what happens to one of these and what is it converted into? what is produced in this conversion? what happens now and how does this allow krebs cycle to continue?
first step of fatty acid synthesis - what is the enzyme? equation?
what is special about this reaction? (2) what drives it?
what inhibits this reaction?
what does acetyl-coa bind to, to allow the reaction to occur?
what 2 other things does the reaction require to occur?
Synthesis occurs in the cytosol, but the formation of citrate initially occurs in the mitochondria. So there needs to be transport of this citrate into the cytosol and this is done by the citrate-malate antiport.
The process is cyclical, because if you removed the mitochondria of all its citrate you would be removing a big component of the Krebs cycle because we are removing oxaloacetate essentially, as it is a cycle.
- The citrate is pumped out into the cytosol and breaks down to give us the Acetyl-CoA and oxaloacetate.
- The oxaloacetate can then be converted to malate which can be converted to pyruvate, importantly in that conversion we produce NADPH (used for FA synthesis).
- The pyruvate is then transported back into the mitochondrion, converted back into oxaloacetate.
The first step in fatty acid synthesis is the rate-limiting step, the enzyme that is involved in this is Acetyl-CoA (x) carboxylase.
Acetyl-CoA + ATP + HCO3- —> malonyl-CoA + ADP + Pi
2c 3c
Via acetyl-CoA carboxylase
The reaction is an important irreversible regulatory step and is driven in part by the amount of citrate that is present = positive feedback.
This makes sense as the amount of citrate in a cell will rise when the flow of glucose through glycolytic pathway is increased.
• The reaction is inhibited by palmitate (negative feedback), which is the end product of fatty acid synthesis.
Note that the Acetyl-CoA binds to a molecule that allows the reaction to occur, this molecule is acyl carrier protein (ACP).
The reaction requires the vitamin biotin to work. The reaction requires ATP.
Acetyl-CoA carboxylase
inhibition and stimulation
what inhibits the enzyme? what stimuates this process hence inhibits the enzyme?
what nutrients ratio will increase or decrease the expression of the enzyme?
Acetyl-CoA carboxylase is inhibited by phosphorylation. Glucagon stimulates phosphorylation and therefore inhibits the enzyme.
Expression of Acetyl-CoA carboxylase is increased by high carbohydrate and low fat.
Expression of Acetyl-CoA carboxylase is decreased by low carbohydrate and high fat.
Fatty acid synthase - importnace
what do all the enzymes required for fatty acid synthesis form? how does it exist?
what is the benefit of this?
what happens with the enzyme as the chain is increased?
what is the importance of intermediates being covalently linked to acyl carrier protein (ACP)? (2)
All the enzymes required for the reactions above form a multi-functional complex called Fatty acid synthase, which exists as a dimer.
• By having a multi-enzyme complex all the reactions to occur are very close to each other and the products of one reaction are very close to the active site of the next enzyme in the chain.
As the fatty acid chain is increased as the enzyme goes around and around in the cycle until the chain reaches the required length and is released.
Importance of intermediates being covalently linked to acyl carrier protein (ACP) is that this enables the efficient and rapid movement of the growing fatty acid chain to be passed from one active site to the next.
Fatty acid synthesis summary
takes place in the fed state when glucose levels are high and demand for ATP is low
Stimulated by insulin
Inhibited by glucagon, adrenalin and noradrenalin
Takes place in a number of tissues but primarily in the liver
Triglycerides are the major storage molecule and is composed of glycerol and free fatty acids
Stored by adipocytes
Cholesterol
what is this? how does it interact with water?
what is it a precursor for? (3)
what else is it used for?
what is it not used for?
how is cholesterol transported in circulation?
- Cholesterol is a rigid hydrophobic molecule that is virtually insoluble in water.
- It is the precursor of sterols, steroids and bile salts.
- It is also an important membrane component.
- It is not an energy-forming molecule.
Cholesterol is transported in the circulation as cholesteryl esters and as mentioned above, cannot be oxidised to O2 and H2O so can provide no energy.
Cholesterol imbalance can lead to significant health issues.
Cholesterol synthesis
where is it synthesised?
how does this process start?
what is a major regulatory step? what enzyme is used? what inhibits this enzyme?
why is it diffcult to reduce circulating cholesterol by diet alone?
- Cholesterol is synthesised mostly in the ER
- There are over 30 steps
- Starts with the activation of acetate to acetyl-CoA.
- So, you can generate cholesterol from a carbohydrate source, like you can generate fatty acids.
- A major regulatory step is the conversion of 3-hydroxyl-3-methylglutaryl CoA (HMGCoA) to mevalonate by HMGCoA reductase.
- Cholesterol inhibits HMGCoA reductase, the enzyme involved in its own synthesis
Therefore, difficult to reduce circulating cholesterol by diet alone as endogenous synthesis is increased. So, you need to tackle it by inhibiting this enzyme and diet.
Fatty Acid Degradation
where are fats synthesised in the liver transported to? how is this done? (2)
how is the fatty acid stored?
what is the first stage in degradation? where does it go after this and what happens here?
Fats synthesised in the liver are transported to the peripheral tissue e.g. adipocytes for storage and this is partly through binding to albumin and partly as lipoproteins.
So, the fatty acid is stored in adipocytes and then the first step then in degradation is mobilising the fatty acid in the adipocyte.
It then gets transported back to the liver and in the cytosol of hepatocytes gets activated.
Then it undergoes degradation in the liver mitochondria, the process is called beta oxidation.
So, the three steps are:
- Step 1: Mobilisation in adipocyte
- Step 2: Activation in hepatocyte cytosol
- Step 3: Degradation in hepatocyte mitochondria
