Lipid synthesis and degradation Flashcards
What essential roles do fats play in the body?
- a role in membranes
- uptake of lipid soluble vitamins
- as precursors of steroid hormones
- energy store
Why is fat such an important store of energy?
The energy content of fat per gram is over twice that of either carbohydrates or proteins, making an important energy source.
When is the synthesis of fat triggered?
When our caloric intake exceeds that of consumption, the excess is laid down as fat.
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.
Describe the structure of fatty acids.
They are chains of methyl groups, with a terminal carboxyl group at one end. If double bonds are present, it is in a cis formation.
Humans are unable to make double bonds at positions less than position 9. That’s why there are ‘essential’ fatty acids that we have to obtain from our diets, as they cannot be made in our bodies.
Palmitic acid (C16) makes up the majority of fatty acids made. If a different number of carbons is required, there are enzymes that will modify it.
Where does fatty acid synthesis take place and what does it require?
Fatty acid synthesis takes place in the cytosol of hepatocytes and it requires:
- Acetyl-CoA
- NADPH
- ATP
It involves the sequential addition of 2 carbon units derived from Acetyl-CoA.
Describe the citrate-malate antiport system and why it is needed.
Pyruvate is transported from the cytosol to the inside of the mitochondrion. There, it is converted to Oxaloacetate, where Acetyl CoA is added to it to create Citrate. Then, the Citrate is brought out of the mitochondrion back into the cytosol, an Acetyl CoA molecule is released from it, turning it back into Oxaloacetate. Then, it is converted to Malate (add NADP), followed by Pyruvate once again (remove NADPH) (additional NADPH is provided by the Pentose Phosphate Pathway).
This is done to transport Acetyl CoA outside of the mitochondrion as it can’t pass through the membrane.
Describe the first step of fatty acid synthesis.
Acetyl-CoA + ATP + HCO3- ——-> Malonyl-CoA + ADP + Pi
It is where Acetyl-CoA (2C) has a carbon molecule added to it by HCO3-, with the help of ATP, changing it to Malonyl-CoA (3C).
It is an important, irreversible, regulatory step activated by Citrate (positive feedforward) and inhibited by Palmitic Acid (negative feedback). It also requires the vitamin Biotin (vitamin B7).
Describe the second step of fatty acid synthesis.
The second part would be fatty acid elongation.
The malonyl residue from Malonyl-CoA is transferred to the Acyl Carrier Protein (ACP) part of the multienzyme complex of fatty acid synthase. A second acetyl molecule from Acetyl CoA is then transferred to ACP where the two condense to form Acetoacetyl-ACP.
The Acetoacetyl-ACP is then reduced and dehydrated to Butyryl-ACP (this requires 2 NADPH molecules). It then combines with another Malonyl-ACP molecule to form the final 6C molecule (and a CO2 molecule).
The intermediates in this reaction are covalently linked to ACP. All enzymes required form a multi-functional complex called Fatty Acid Synthase. This exists as a dimer.
Describe the structure and functions of cholesterol.
It is a rigid, hydrophobic molecule that is virtually insoluble in water. It is an important membrane component, and a precursor of sterols, steroids and bile salts.
It is transported in the circulation as cholesteryl esters. It can’t be oxidised to O2 or H2O, so it provides no energy.
Cholesterol imbalance can lead to significant health issues, such as gallstones and atherosclerosis
Briefly, describe cholesterol synthesis.
Cholesterol is synthesised in the ER (with over 30 steps involved).
It starts with the activation of Acetate in Acetyl-CoA. The major regulatory step is the conversion of 3-hydroxyl-3-methyl-glutaryl CoA (HMG-CoA) to Mevalonate.
Cholesterol inhibits HMG-CoA reductase, an enzyme involved in its own synthesis.
It’s difficult to remove circulating cholesterol by diet alone as endogenous synthesis is increased.
What are the three steps of Fatty Acid Degradation?
1) MOBILISATION
2) ACTIVATION
3) DEGRADATION
Describe Fatty Acid Mobilisation.
A G-protein coupled receptor activates Adenylate Cyclase that increases the amount of cAMP made from ATP, which, in turn, activates Protein Kinase.
This Protein Kinase activates Triacylglycerol Lipase.
This converts Triacylglycerol to Diacylglycerol.
The Diacylglycerol is then broken down into Glycerol and Fatty Acids.
What becomes of the glycerol mobilised in Fatty Acid Mobilisation?
It is absorbed by the liver. In there, it follows a series of steps to convert it to GAP (Glyceraldehyde-3-phosphate):
1) Glycerol is phosphorylated to Glycerol-3-Phosphate.
2) Glycerol-3-Phosphate is oxidised by Dihydroxyacetone Phosphate.
3) Dihydroxyacetone Phosphate is isomerised to Glyceraldehyde-3-Phosphate (GAP).
The majority of GAP goes towards GLUCONEOGENESIS, and a bit of it goes towards GLYCOLYSIS.
What is Fatty Acid Activation?
It is when fatty acids are transported to the liver and activated by Acyl-CoA Synthase in the cytoplasm. The Acyl-CoA produced is transported across the inner mitochondrial membrane bound to the alcohol Carnitine.
Describe Fatty Acid Activation.
In the cytoplasm, the Acyl-CoA will react with carnitine to give Acyl-Carnitine, which can then be transported across the membrane through the action of the enzyme Translocase. The Acyl-Carnitine is then broken down back into Carnitine, releasing the Acyl to combine with the CoA, remaking Acyl-CoA in the mitochondria. This allows the molecule to get across the membrane.
Carnitine deficiency can cause muscle weakness or even death.
The transport is also inhibited by Malonyl-CoA, which is a step in the synthesis of fatty acids. So if it builds up, we will be moving towards synthesis, meaning this degradation transport process is inhibited.
