S2: Lipid Synthesis and Degradation

Question 1

How are fats obtained?

Answer 1

• In the diet

- Made de novo from carbohydrates

Question 2

Roles of fats

Answer 2

• Membranes
• Important in uptake of fat soluble vitamins
• Used as precursors for steroid hormones
• Energy store

Question 3

Compare energy content of fat, protein and carbohydrate

Answer 3

Fat>Protein>Carbohydrate

Question 4

List 3 main types of fat

Answer 4

• Fatty acids
• Triglycerides or Neutral Fats
• Cholesterol

Question 5

What is the preferred energy source?

Answer 5

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

Question 6

Structure of fatty acid

Answer 6

• 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

Question 7

Example of saturated fatty acid

Answer 7

Palmitate

Question 8

Example of unsaturated fatty acid

Answer 8

Oleate

Question 9

How is lipid synthesis and degradation an example of compartmentalisation?

Answer 9

-Mostly occur in liver hepatocytes

Synthesis= occurs in the cytosol
Breakdown (beta oxidation)= occurs in the mitochondria

Question 10

How are lipid synthesis and degradation regulated?

Answer 10

Reciprocally regulated

Synthesis during excess calorie intake and breakdown is inhibited

During breakdown then synthesis is inhibited

Question 11

Structure of triglycerides

Answer 11

They are neutal fats- most fats are stored in this way

• 3 fatty acids attached to a glycerol backbone
• Stores of energy

Question 12

How can glycerol be made?

Answer 12

Glycerol can be made from glycolysis by glycerol-3-phosphate, glycerol can also be fed into glycolysis at this point.

Question 13

What is the starting block for the synthesis of fatty acid?

Answer 13

ACoA

Question 14

How is fatty acids made from ACoA?

Answer 14

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)

Question 15

How can cholesterol be made?

Answer 15

From ACoA

Cholesterol is then transported to various tissues to be incorporated into membranes or for steroid synthesis

Question 16

Where does fatty synthesis occur and what are the 3 substrates required?

Answer 16

It occurs in the cytosol.

Fatty acid synthesis requires:

• Acetyl CoA
• NADPH
• ATP

Question 17

Explain the transfer of acetyl CoA to cytosol

Answer 17

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

Question 18

Explain the first step of fatty acid synthesis

Answer 18

• 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)

Question 19

What regulates the enzyme Acetyl CoA carboxylase?

Answer 19

• 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

Question 20

Explain fatty acid synthesis - Elongation

Answer 20

• 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)

Question 21

What happens after elongation in the synthesis of fatty acids?

Answer 21

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.

Question 22

Where does the NADPH come from in the synthesis of fatty acids?

Answer 22

It is either generated through the citrate-malate transporting or the pentose-phosphate pathway

Question 23

What is fatty acid synthase?

Answer 23

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.

Question 24

What is cholesterol and how is it transported?

Answer 24

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.

Question 25

What is cholesterol a precursor for?

Answer 25

Sterols Steroids Bile Salts

Question 26

Can cholesterol provide energy?

Answer 26

No | It cannot be oxidised to O2 and H2O

Question 27

Describe cholesterol synthesis

Answer 27

- 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

Question 28

What inhibits HMGCoA reductase and what is the consequence of this?

Answer 28

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.

Question 29

Explain fatty acid degradation

Answer 29

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

Question 30

What is the liver's main energy source?

Answer 30

Lipids/fatty acids

Question 31

Explain mobilisation of fatty acids

Answer 31

- 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

Question 32

What is the fate of glycerol?

Answer 32

The glycerol is absorbed by the liver and can be converted back to glucose (gluconeogenesis) or converted to pyruvate (glycolysis)

Question 33

Explain activation of fatty acids

Answer 33

-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

Question 34

What enzyme activates fatty acids in the hepatocyte cytoplasm?

Answer 34

Acyl-CoA synthase

Question 35

What inhibits the transportation of activated fatty acid (Acyl CoA) across inner mitochondrial membrane?

Answer 35

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.

Question 36

Explain fatty acid oxidation (beta oxidation) which is step 3 of fatty acid degradation

Answer 36

- 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

Question 37

Explain ketogenesis

Answer 37

- ACoA --> Ketone bodies 1. Acetyl-CoA from breakdown of fatty acids is converted to acetocacetyl-CoA 2. Acetoacetyl-CoA is converted to HMG-CoA (by enzyme B-hydroxy-B-methyglutaryl-CoA) 3. 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).

Question 38

What is the fate of ketone bodies?

Answer 38

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.

Question 39

Explain hormonal regulation of fat metabolism

Answer 39

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