Lipid Synthesis and Degradation

Question 1

Why are fats considered an essential part of the diet?

Answer 1

As it acts as a primary fuel for many tissues including cardiac myocytes. It is also needed for the absorption of fat soluble vitamins.

Question 2

Where does fatty acid synthesis take place on a cellular level?

Answer 2

In the cytoplasm (cytosol) in cells.

Question 3

Where does degradation take place on a cellular level?

Answer 3

In mitochondria found in cells.

Question 4

Where are fats obtained from?

Answer 4

Either from diet or made de novo from carbohydrates.

Question 5

Why are fats important?

Answer 5

They play an essential role in many biological functions including:

• forming membranes
• uptake of lipid soluble vitamins
• as precursors of steroid hormones e.g. cholesterol
• energy store: the energy content of fat per gram is twice more of the energy content of protein or carbohydrate.
• 1g fat- 37 kJ
• 1g protein- 17 kJ
• 1g carbohydrate- 16 kJ

Question 6

When are fatty acids synthesised?

Answer 6

When calorific intake exceeds the consumption.

Question 7

Where in the body does fatty acid synthesis take place?

Answer 7

Mostly synthesised in the liver but is stored as adipose tissue which can be found around the body.

Question 8

What are fatty acids?

Answer 8

They are chains of methyl group with a terminal carboxyl group.
They can have double bonds and if present are usually in cis conformation (however humans are unable to create double bonds less than position 9).
Essential fatty acids are obtained from the diet.

Question 9

What is the major product created from fatty acid synthesis?

Answer 9

Major product of fatty acid synthesis is Palmitic acid – from this we have ways of modifying using enzymes the basic molecule into different fatty acids we have. It is C60 and carbons can be added or removed as well as bonds etc.

Question 10

What is required for fatty acid synthesis?

Answer 10

• Acetyl CoA
• NADPH- the majority comes from pentose phosphate pathway- this pathway is active when excess glucose is present.
• ATP
• primarily fatty acid synthesis is the sequential addition of 2 two carbon units derived from acetyl CoA.

Question 11

How is fatty acid synthesised from glucose

Answer 11

LOOK AT NOTES FOR THE DIAGRAM.

• Pyruvate enters the mitochondria and converted to oxaloacetate.
• This combines with Acetyl CoA to form citrate.
• The citrate is transported out and cleaved to form acetyl CoA and oxaloacetate.
• The oxaloacetate is converted to malate and then pyruvate -in doing so NADPH is produced. These transportations lead to forming two important molecules: Acetyl CoA and NADPH. Additional NADPH (over 60% from this pathway)is provided by pentose phosphate pathway.

Question 12

How is acetyl CoA transferred into the cytosol?

Answer 12

-This process is called Citrate-malate antiport – more than 40% of NADPH is formed this way
FIRST STEP:
Acetyl-CoA+ATP+HCO3 —> malonyl-CoA+ADP+Pi
^
Acteyl-CoA carboxylase
-This is an important irreversible regulatory step which is activated by citrate (positive feed forward) and inhibited by the product – largely Palmitic acid (negative feedback). This requires the vitamin biotin.
-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.
SECOND STEP:
LOOK AT NOTES FOR THE DIAGRAM
-First step is acetyl-CoA carboxylase to form malonyl-CoA then the malonyl residue is transferred to the acyl carrier protein (ACP) part of the multi-enzyme 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 enzyme for fatty acid synthesis is called fatty acid synthase and is a very large molecule – it exists as a dimer to make the synthesis as efficient as possible. All the enzymes required form a multi-functional complex called Fatty acid synthase. There are number of different active sites required for the synthesis.
-The product binds to fatty acid synthase and is passed from each active site to another with the end result of adding 2 carbons that would be passed to the start of the reaction to the adjacent enzyme.
-The glycerol will ultimately convert to glyceraldehyde 3-phosphate- in hepatic tissue this will largely go to the formation of pyruvate i.e. glycolysis. Live will convert this to glucose and release into the blood (gluconeogenesis).

Question 13

What happens during fatty acid degradation?

Answer 13

• Fatty acids are transported to the liver and activated by acyl-CoA synthase in the cytoplasm
• Acyl-CoA produced is transported across the inner mitochondrial membrane bound to the alcohol carnitine
• Step 2: Activation – liver cytosol
• Long chain FA activated following reaction with CoA to give acyl-CoA – ATP OMM
• Transported to inner mitochondrial matrix for oxidation using carnitine
• Carnitine deficiency can cause muscle weakness or even death
• Acyl CoA reacts with carnitine to give acyl carnitine and transported into the mitochondria and converted back to carnitine. Transport mechanism to get fatty acids to IMM space where the enzymes are present to break down fatty acid degradation. This transport is inhibited by malonyl-CoA – so large amount of this prevents breakdown when excess glucose present.
• Step 3: Degradation – liver mitochondria

Question 14

What happens in fatty acid oxidation in liver mitochondria?

Answer 14

• Acyl-CoA degraded by removal of two carbon units
• As a result FADH2, NADH and acetyl-CoA are produced
• FADH2 and NADH can be used for glycolysis
• This cycle continues

Question 15

What happens in fatty acid oxidation (b-oxidation)?

Answer 15

-FADH2 and NADH form ATP
-The Acetyl-CoA enters the citric acid cycle only in the presence of glycolysis
-Complete oxidation of Palmitic acid will give 106 molecules of ATP – significant amount of energy for a single fatty acid.
-Odd chain length yield propionyl-CoA in the last round of oxidation
-Odd numbered double bonds are removed by isomerase even double bonds by reductase and isomerase
-The acetyl-CoA in hepatocytes is converted to ketone bodies and these are transported to non-hepatic tissue for metabolism.
LOOK AT DIAGRAM

Question 16

What happens during ketogenesis?

Answer 16

• Acetyl-CoA is converted to acetoacetyl-CoA
• Acetoacetyl-CoA converted to HMG-CoA (β-hydroxy β-methylglutaryl-CoA)
• HMG-CoA converted to acetoacetate (ketone bodies)
• Acetoacetate can be reduced to 3-β-hydroxybutyrate 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).

Question 17

What is the fate of the ketone bodies?

Answer 17

Major energy source for cardiac muscle and renal cortex - dependent on the flow of carbohydrate in glycolysis
During starvation up to 75% of the brains energy is derived from acetoacetate

Question 18

How a hormones regulated by fat metabolism?

Answer 18

-Insulin
↑ glycolysis in the liver
↑ Fatty acid synthesis in the liver
↑ TG in adipose tissue
↓ b-oxidation
-Glucagon and adrenaline
↑ TG mobilisation