S2: Lipid Synthesis and Degradation Flashcards
How are fats obtained?
- In the diet
- Made de novo from carbohydrates
Roles of fats
- Membranes
- Important in uptake of fat soluble vitamins
- Used as precursors for steroid hormones
- Energy store
Compare energy content of fat, protein and carbohydrate
Fat>Protein>Carbohydrate
List 3 main types of fat
- Fatty acids
- Triglycerides or Neutral Fats
- Cholesterol
What is the preferred energy source?
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.
Dietary carbohydrate is the most common source of metabolic building blocks although some amino acids can also be used
Structure of fatty acid
- Fatty acid are chains of methyl groups with a carboxyl group at the end (terminal)
- Fatty acids can be saturated with single bonds or unsaturated with double bonds
- Humans unable to create double bonds in positions less than 9- these essential fatty acids must be obtained from diet
Example of saturated fatty acid
Palmitate
Example of unsaturated fatty acid
Oleate
How is lipid synthesis and degradation an example of compartmentalisation?
-Mostly occur in liver hepatocytes
Synthesis= occurs in the cytosol
Breakdown (beta oxidation)= occurs in the mitochondria
How are lipid synthesis and degradation regulated?
Reciprocally regulated
Synthesis during excess calorie intake and breakdown is inhibited
During breakdown then synthesis is inhibited
Structure of triglycerides
They are neutal fats- most fats are stored in this way
- 3 fatty acids attached to a glycerol backbone
- Stores of energy
How can glycerol be made?
Glycerol can be made from glycolysis by glycerol-3-phosphate, glycerol can also be fed into glycolysis at this point.
What is the starting block for the synthesis of fatty acid?
ACoA
How is fatty acids made from ACoA?
ACoA is converted into citrate in the Kreb cycle
Citrate is transported out of the mitochondria and into cytosol
ACoA then removed from citrate
This is converted into fatty acids
Fatty acids can remain in the liver (liver lipids) or be exported bound within lipoproteins or bound to albumin as free fatty acid (transported to peripheral tissue e.g. adipocytes for storage)
How can cholesterol be made?
From ACoA
Cholesterol is then transported to various tissues to be incorporated into membranes or for steroid synthesis
Where does fatty synthesis occur and what are the 3 substrates required?
It occurs in the cytosol.
Fatty acid synthesis requires:
- Acetyl CoA
- NADPH
- ATP
Explain the transfer of acetyl CoA to cytosol
This is done using the citrate-malate antiport
The process is cylindrical:
- Citrate pumped into cytosol
- Breaks down to give ACoA and oxaloacetate
- Oxloacetate can be converted to malate which can be converted into pyruvate (NADPH produced in the last step)
- Pyruvate is then transported back into mitochondrion and converted into oxaloacetate
- This can combine with ACoA to Citrate thus completing the cycle
Explain the first step of fatty acid synthesis
- This is the rate limiting step
- ACoA binds to acyl carrier protein (ACP)
Acetyl CoA + ATP + HCO3- –*—> Malonyl CoA + ADP + Pi
- C2 to C3
- Enzyme used is *Acetyl CoA carboxylase
- Requires ATP and vitamin biotin
Positive feedback: Citrate (rise when flow of glucose through glycolytic pathway increases)
Negative feedback: Palmitate (end product of fatty acid synthesis)
What regulates the enzyme Acetyl CoA carboxylase?
- Inhibited by phosphorylation. Glucagon stimulates phosphorylation which therefore inhibits the enzyme.
ACoA carboxylase is increased by high carbohydrate and low fat
ACoA carboxylase is decreased by low carbohydrate and high fat
Explain fatty acid synthesis - Elongation
- C2 to C4
The first rate limiting step produces malonyl CoA that reacts with ACP (acyl carrier protein) to form Malonyl ACP (3C molecule)
Acetyl ACP and Malonyl ACP undergo a condensation reaction releasing CO2 producing Acetoactyl-ACP (4C molecule)
What happens after elongation in the synthesis of fatty acids?
There are then three reactions that occur, a reduction, a dehydration and then another reduction coming out still as a 4C molecule of Butyryl-ACP.
The Butyryl ACP then reacts with a further Malonyl-ACP in a condensation reaction with the generation of a second CO2, now we have a 6-carbon molecule.
Where does the NADPH come from in the synthesis of fatty acids?
It is either generated through the citrate-malate transporting or the pentose-phosphate pathway
What is fatty acid synthase?
All the enzymes required for fatty acid synthesis form a multi-functional complex called fatty acid synthase which exists as an 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.
What is cholesterol and how is it transported?
It is a rigid hydrophobic molecule that is virtually insoluble in water. It is an important membrane component.
It is transported in the circulation as cholesteryl esters.
What is cholesterol a precursor for?
Sterols
Steroids
Bile Salts
Can cholesterol provide energy?
No
It cannot be oxidised to O2 and H2O
Describe cholesterol synthesis
- Mainly occurs in the ER
- Over 30 steps
- Starts with the activation of acetate to acetyl-CoA so cholesterol can be generated from a carbohydrate source similar to the synthesis of fatty acids
- Target for therapeutic interventions: convertion of 3 hydroxyl-3-methylglutaryl CoA (HMGCoA) to mevalonate by HMGCoA reductase
What inhibits HMGCoA reductase and what is the consequence of this?
Cholesterol inhibits HMGCoA reductase, the enzyme involved in its own synthesis
It is therefore difficult to reduce circulating cholesterol by diet alone as endogenous synthesis is increased. This problem therefore needs to be tackled by inhibiting the enzyme and diet.
Explain fatty acid degradation
It is the release of energy from reserves stored in adipose tissue
Step 1: Mobilisation of fatty acid in adipocyte where it is transported back to the liver
Step 2: Activation of fatty acids in hepatocyte cytosol by acyl-CoA synthase
Step 3: The fatty acid is degraded in the liver mitochondria in the process called beta oxidation
What is the liver’s main energy source?
Lipids/fatty acids
Explain mobilisation of fatty acids
- Stimulation of the 7TM G-protein coupled receptor by glucagon or adrenaline
- cAMP activates PKA
- Phosphorylation of triacylglycerol lipase which breaks down triacylglycerol to diacylglycerol
- Diacylglycerol further acted upon by lipases leading to free fatty acids and glycerol which can diffuse through the plasma membrane leaving the adipocyte
This step is important when food is not readily available i.e. Starvation or excersize stimulated by glucagon and adrenaline but inhibited by insulin
What is the fate of glycerol?
The glycerol is absorbed by the liver and can be converted back to glucose (gluconeogenesis) or converted to pyruvate (glycolysis)
Explain activation of fatty acids
-Fatty acids are transported to the liver and activated by acyl-CoA synthase in the cytoplasm
- This gives Acyl-CoA by activation and it is then transported across the inner mitochondrial membrane (enzyme translocase) bound to the alcohol carnitine
’
Cartinine deficiency can cause muscle weakness or death
What enzyme activates fatty acids in the hepatocyte cytoplasm?
Acyl-CoA synthase
What inhibits the transportation of activated fatty acid (Acyl CoA) across inner mitochondrial membrane?
The transport is also inhibited by malonyl-CoA which is the first thing in the synthesis of fatty acids. So if it builds up, we will be moving towards synthesis so this degradation transport process is inhibited.
Explain fatty acid oxidation (beta oxidation) which is step 3 of fatty acid degradation
- occurs in liver mitochondria
- Acyl-CoA degraded by removal of 2C units by B oxidation
- FADH2, NADH and acetyl-CoA are produced
- FADH2 and NADH form ATP
- ACoA tend to be converted to ketone bodies but can also enter into CCA cycle (in presence glycolysis) and form ATP
There is cleaving of fatty acid until it reaches a certain chain length
Odd length: proprionyl CoA. Odd numbered double bonds are removed by isomerase
Even numbered double bonds are removed by reductase and isomerase
Explain ketogenesis
- ACoA –> Ketone bodies
- Acetyl-CoA from breakdown of fatty acids is converted to acetocacetyl-CoA
- Acetoacetyl-CoA is converted to HMG-CoA (by enzyme B-hydroxy-B-methyglutaryl-CoA)
- HMG-CoA converted to acetoacetate
The 3 ketone bodies: Acetoacetate can be reduced to 3-β-hydroxybuterate or non-enzymatically to acetone
The synthesis of ketone bodies are regulated by the insulin/glucagon ratio. Ketogenesis is high when the ratio is low as this inhibits acetyl-CoA carboxylase (rate limiting step in fatty acid synthesis).
What is the fate of ketone bodies?
Acetoacetate is converted in the non-hepatic tissue back to acetyl-CoA, this can then be used to generate ATP.
Ketone bodies are a major energy source for cardiac muscle and renal cortex dependent on flow of carbohydrate in glycolysis (glucose is preferred).
During starvation or diabetes 75% of the brains energy is derived from acetoacetate – the production of ketones increases with decreased food intake.
Explain hormonal regulation of fat metabolism
Insulin
- Increases glycolysis
- Increases fatty acid synthesis in the liver
- Increases TG storage in adipose tissue
- Decreases beta oxidation
Glucagon and Adrenaline
- Increases TG mobilisation
- Inhibits fatty acid synthesis
