lipid synthesis and degredation

Question 1

what can fats be made of and where are they stored ?

Answer 1

• Fats are most often made from dietary carbohydrates
• However some amino acids can also be used
• Not all fats are stored as they are also the preferred energy source for cardiac muscle
• Fats are stored in the adipose tissue as triglycerides but the majority are synthesised in the liver
• Triglycerides are formed from glycerol and 3 fatty acids

Question 2

describe the properties of fatty acids

Answer 2

• Chains of methyl groups
• Terminal carboxyl group
• Double bonds if present are usually in cis conformation
• Humans unable to create double bonds less than position 9
• Essential fatty acids obtained from the diet.

Question 3

where are the majority of fatty acids synthesised

Answer 3

• Majority of fatty acids synthesised in the body are synthesised by the liver
• They are synthesised mainly from excess glucose taken up from the diet

Question 4

what happens when glucose enters the cell in the liver.

Answer 4

, glucose enters the cell and is phosphorylated to give g-6-p, in the liver, this is performed by the enzyme glucokinase.
- The g-6-p is further metabolised to form pyruvate. Pyruvate is then converted to acetyl Co A and react with oxaloaetic acid to form citrate. -TCA cycle

Question 5

what happens when the levels of ATP are high and the need for glucose is low?

Answer 5

the excess citrate is transported out of the mitochondria where it is converted back to Acetly-CoA and is synthesised into fatty acids.
- The fatty acids will either be retained in the liver but the majority will be transported in the blood as lipoproteins or free fatty acids bound to albumin, and transported to non-hepatic tissues such as adipocytes for storage.

• OR
• The acetyl Co A can be used to synthesise cholesterol which is transported around the body to non-hepatic tissue.

Question 6

where does fatty acid take place, what does it require and what does it involve

Answer 6

Takes place in the cytosol and requires:
•	Acetyl-CoA
•	NADPH
•	ATP
It involves the sequential addition of 2 two carbon units derived from acetyl-CoA.

Question 7

describe the transfer of acetly coA to the cytosol form the mitochondria

Answer 7

• This requires the citrate-malate antiporter
• Acetyl coA reacts with oxaloacetate acid to form citrate.
• The citrate is then transported out of the mitochondria to the cytosol where the acetyl coA is regenerated with oxaloacetic acid.
• Oxaloacetic acid is then converted to malate which is converted to pyruvate, forming NADPH in the process.
• The pyruvate is transported back into the mitochondria where it is converted to oxaloacetetic acid and the cycle repeats.

Question 8

what is a vital componant of fatty acid synthesis and what provides it

Answer 8

• NADPH

– Citrate malate shuttle provides 40% NADPH needed for fatty acid synthesis 60% comes from the pentose phosphate pathway

Question 9

recall about the first step of fatty acid synthesis

Answer 9

Important irreversible regulatory step, activated by citrate (positive feed forward) and inhibited by the product of the reaction- palmitic acid (negative feedback)
this requires the vitamin biotin
the enzyme required -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.

Question 10

outline the steps in fa synthesis

Answer 10

1. Acetyl coA (2C) combines with carbonate to form malonyl-CoA.
2. Malonyl-CoA then reacts with ACP(acyl carrier protein ) to form Malonyl-ACP (3C). This activates Malonyl-CoA so that it can undergo further reactions.
3. It undergoes a reaction with a 2nd molecule of acetyl-CoA.
4. The acetyl-CoA then reacts with a Acetly-ACP
5. The acetyl-ACP reacts with malonyl-ACP In a condensation reaction which leads to the loss of C02, and forms acetoactyl-ACP.(c4)
6. It then undergoes reduction, dehydration and reduction to form Butyryl-ACP (C4)
7. Butyryl-ACP will then react with another acetyl-coA which ( just like before) forms malonyl -CoA which reacts with ACP to form malonyl-ACP (C3) .
8. Malonyl-ACP then combines with butyryl-ACP to produce C02 and a 6C molecule.
9. This process require the use of NADPH

Question 11

which protein is responsible for fa synthesis? and what is its function?

Answer 11

fatty acid synthase

-brings together the substrate and the enzyme active site
• Intermediates are covalently linked to acyl carrier protein (ACP)
• This enables the efficient and rapid movement of the growing fatty acid chain to be passed from one active site to the next.
• The efficiency of the reaction is further enhanced as the enzyme exists as a dimer arranged head to tail. So as the growing fatty acid chain is passed from one dimer to the other, the reaction is more efficiently regulated.

Question 12

when does fa synthesis occur?

Answer 12

takes place in the fed state when glucose levels are high and demand for ATP is low

Question 13

what is fa synthesis stimulated and inhibited by?

Answer 13

Stimulated by insulin

Inhibited by glucagon, adrenalin and noradrenalin

Question 14

what are fatty acids transported as ?

Answer 14

Fatty acids are transported as Triglycerides which are the major storage molecules and is composed of glycerol and free fatty acids
Triglycerides are primarily Stored in adipocytes

Question 15

describe cholesterol

Answer 15

• Rigid hydrophobic molecule virtually insoluble in water
• Precursor of sterols, steroids and bile salts
• Important membrane components
• Transported in the circulation as cholesteryl esters
• Cannot be used to provide energy
• Cholesterol imbalance can lead to significant health issues

Question 16

where is cholesterol mostly synthesised ?

Answer 16

er

Question 17

what is the major regulatory step in fa synthesis ?

Answer 17

• Major regulatory step is the conversion of 3-hydroxyl-3-methylglutaryl CoA (HMGCoA) to mevalonate
• Cholesterol inhibits HMGCoA reductase, the enzyme involved in its own synthesis

Question 18

why is it difficult to reduce circulating cholesterol by diet alone?

Answer 18

• 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

Question 19

what are the 3 steps involved in the release of energy from reserves stored in adipose tissue

Answer 19

Step 1 Mobilisation – of triglycerides from adipocyte
Step 2 Activation – of fatty acids in the liver cytosol
Step 3 Degradation – of fatty acids in the liver mitochondria

Question 20

explain how fatty acids are mobilised ?

Answer 20

• Hormones that stimulate the mobilisation of fatty acids are glucagon and adrenalin.
• These act through 7 transmembrane domain receptors, resulting in the increase of cAMP.
• cAMP will then activate protein kinase A
• protein kinase A will then phosphorylate and activate triacylglycerol lipase.
• Triacylglycerol lipase will then break down triglycerides into diacylglycerol and free fatty acids.
• Following the activity of lipases, there is the release of glycerol and further free fatty acids, which are then transported back to the liver for metabolism.

Question 21

explain how fatty acids are activated

Answer 21

Fatty acids are transported to the liver and activated by acyl-CoA synthase in the cytoplasm to form fatty acyl-CoA.
• Fatty acyl-CoA reacts with the alcohol carnitine to form fatty acyl-carnitine. This is required in order to be transported from the cytosol into the mitochondria.
• Fatty acyl-carnitine is then transported across the inner mitochondrial membrane via translocase
• Acyl carnitine is then broken down to form carnitine and acyl CoA.

Question 22

describe how fatty acid/beta oxidation occurs.

Answer 22

• Fatty acid oxidation/breakdown occurs in the mitochondria of the liver.
  • Acyl-CoA degraded by sequential removal of two carbon units
  • As a result FADH2, NADH and acetyl-CoA are produced. NADH and FADH2 are used by cells to produce ATP, and the acetyl co-A can be used in the TCA cycle in some cells, or in the liver to form ketone bodies.

Question 23

what inhibits the transport of acyl-carnitine

Answer 23

malonyl-CoA – the product formed during fatty acid synthesis.

Question 24

in non-hepatic tissue what does the complete oxidation of palmitate yield?

Answer 24

106 molecules of atp

Question 25

what does an odd chain length yield in the last round of oxidation

Answer 25

• Odd chain length yield propionyl-CoA instead of acetyl-coA
• Propionyl-CoA is converted to oxaloacetate and used for gluconeogenesis and generate glucose

Question 26

what are the odd number of doubles bonds removed by and what are the even number of doubles removed by ?

Answer 26

• Odd number of double bonds are removed by isomerase and even number of double bonds are removed first by reductase and then isomerase

Question 27

in the liver what is the main product of beta oxidation used for , and in the cardiac and skeletal muscle what is it used for ?

Answer 27

• In the liver the main product acetyl-CoA is used for ketogeneis.

– In the cardiac and skeletal muscle, used to make ATP.

Question 28

when and why does the liver produce ketone bodies from acetly co-a

Answer 28

Occurs during Fasting, uncontrolled diabetes and prolonged exercise stimulates fatty acid breakdown producing acetyl-CoA. Under these circumstances, the prime function of the liver is to maintain blood glucose levels via gluconeogenesis. During the process of gluconeogenesis, the concentration of oxaloacetic acid is depleted. This means that acetyl co-A produced by beta oxidation is channeled into the production of ketone bodies.

Question 29

give 3 ketone bodies

Answer 29

ketone bodies are acetoacetate, 3-β-hydroxybutyrate and acetone – formed by ketogenesis.

Question 30

how is the synthesis of ketone bodies regulated ?

Answer 30

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 31

outline the steps in ketogenesis

Answer 31

1. 2 molecules of acetyl-coA combine to form acetoacetyl-CoA
2. Acetoacetly-coA combines with acetyl-coA +H20 to form 3-hydroxy 3-methylglutaryl-CoA (HMG-CoA). This is catalysed by the enzyme HMG-CoA synthase.
3. HMG-CoA then is cleaved to form Acetly-CoA and acetoacetate.
4. Acetoacetate can either be converted to 2 products.

Question 32

what is the fate of ketone bodies

Answer 32

• Preferentially used by cardiac muscle and renal cortex

- Used by the brain during starvation

Question 33

explain how the ketone bodies are metabolised in the tissue

Answer 33

• 3-beta-hydroxybutyrate can be converted back to acetoacetate.
• Acetoacetate can then react with succinyl-CoA to form acetoacetly-CoA.
• This then reacts with CoA to form 2 molecules of acetyl-CoA.
• This can then enter the TCA cycle and be used for the production of ATP.

Question 34

what is the fate of glycerol in the liver and in the muscle

Answer 34

Breakdown of triglycerides gives acetyl-CoA and glycerol
In the liver glycerol is used to synthesis glucose by gluconeogenesis .
- The glycerol is converted to glyceraldehyde 3-phosphate is then converted to glucose
In the muscle glycerol is used in glycolysis and oxidative phosphorylation to produce ATP
- Glyceraldehyde 3-phosphate undergoes the remaining path of glycolysis.

Question 35

what are fatty acids broken down to form

Answer 35

• FA are broken down in a step by step manner in to acetyl CoA

Question 36

describe the hormonal regulation of fat metabolism

Answer 36

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

Question 37

compare the synthesis and degradation of fatty acids

Answer 37

synthesis - cytosol, degredation -mitochondria, s- intermediates linked to acyl-carrier protein, d- intermediates linked to coenzyme a, s- sequential addition of 2c, d- sequential removal of 2C, s- reductant NADPH, d- oxidants FAD and NAD,
s- fatty acid synthase complex, d-carried out by indiviual enzymes.

Question 38

glycerol is fed into - in muscle or - in the liver

Answer 38

glycolysis /gluconeogenesis.

Question 39

• In the liver FA are activated and transported to - where they undergo - to form acetyl coA . the acetyl coa in the liver is then converted to - which is transported around the body for use in circusmtambces where -

Answer 39

mitochondria, beta oxidation, ketone bodies, circulating blood glucose levels are low .