Lecture 19 - Lipids as a source of energy

Question 1

What are adipocytes?

Answer 1

Adipocytes are a type of cells containing where lipids are stored as triacylglycerols

Lipids are very highly reduced which means there is lots of energy released when they are oxidised. They are a more effective energy source in comparison to carbohydrates

Question 2

How are lipids ingested and stored by the body?

Answer 2

In the lumen triglycerides form micelles and are broken down into fatty acids and monoacylglycerols by pancreatic lipases and bile salts. They can then diffuse through the cell membrane into the cytoplasm of mucosal cells.
Within the mucosal cells they reform triacyl-glycerides and are then combined with other lipids and proteins to form chylomicrons which are then transported to the lymph system and to the blood where they are either stored in adipocytes or used immediately in the muscle.

Question 3

Describe the signalling pathways and enzymes involved in lipid breakdown.

Answer 3

Upon hormone binding to GPCR a heterotrimeric G-protein is activated (the GDP is replaced with GTP). It then activates adenylates cyclase which leads to a rapid rise in cAMP concentration. The cAMP activates Protein Kinase A. The Protein kinase activates lipases via phosphorylation.

* Perilipin is activated which subsequently activates ATGL (Adipose triglyceride lipase) which catalyses the breakdown of the Triacylglycerol into a Diacylglycerol.
* HS lipase (Hormone sensitive lipase) is activated and catalyses the removal of another fatty acid breaking down the DAG into a MAG (Monoacylglycerol)
* Monoacylglycerol lipase removes the final fatty acid from the glycerol backbone to form fatty acid and glycerol as the final products.  Activated by epinephrine and inhibited by insulin

Question 4

Describe the process of fatty acid degradation.

Answer 4

Fatty acid degradation (the reverse of synthesis)

1. Oxidation 1 (FAD)
Acyl CoA dehydrogenase (3 isoenzymes - different for different lengths) catalyses the oxidation of acyl CoA to trans-Δ2-Enoyl CoA
Puts a trans carbon carbon double bond at C2

2. Hydration
Enoyl CoA hydratase hydrates the trans-Δ2-Enoyl CoA to L-3-Hydroxyacyl CoA
The fact it is originally a trans bond is important or else we would get the D-isomer

3. Oxidation 2 (NAD)
L-3-hydroxyacyl CoA dehydrogenase catalyses the oxidation of the L-3-hydroxyacyl CoA to 3-keotacyl CoA

4. Thiolysis
β-Ketothiolase catalyses the thiolysis of 3-ketoacyl CoA into Acyl CoA (shortened by two carbons) and Acetyl CoA The Acetyl CoA produces can then go on to be used in the citric acid cycle or to produce ketone bodies. The Acyl CoA then repeats the cycle losing two carbons each time until Acetyl CoA is produced. 

Example: Palmitoyl CoA
The complete oxidation of palmitate produces 106 molecules of ATP as the products of 8 molecules of Acetyl CoA is fed into the citric acid cycle. ATP is also produced from the NADH and FADH2. 2 ATP are used for palmitate activation to palmitoyl CoA.

Question 5

Describe the breakdown of unsatturated fatty acids.

Answer 5

When a lipid has double bond additional enzymes are needed depending on the location of the double bonds.
Odd numbered C=C bonds require an isomerase
Even numbered C=C bonds require both a isomerase and reductase

Odd numbered C=C bonds
Palmitoyl CoA with a double bond on carbon 9 after 3 cycles (losing 2C and producing one molecule of acetyl CoA each cycle) forms cis-Δ3-Enoyl CoA
* Cis-Δ3-Enoyl CoA is not a substrate for acyl CoA dehydrogenase
* Cis-Δ3-enoyl CoA isomerase changes the location of the double bond forming trans-Δ2-Enoyl CoA which is a substrate

Even numbered C=C bonds
Linoleoyl CoA has two double bonds. It is able to go through 3 cycles forming 3 molecules of acetyl CoA and Cis-Δ3,cis-Δ6-dienoyl CoA.
* Cis-Δ3,cis-Δ6-dienoyl CoA is not a substrate for acyl CoA dehydrogenase
* Cis-Δ3-enoyl CoA isomerase changes the location of the double bond forming trans-Δ2,cis-Δ6-dienoyl CoA which is a substrate
* trans-Δ2,cis-Δ6-dienoyl CoA is a substrate for Enoyl CoA hydratase and is able to finish it fourth round of oxidation forming cisΔ4-acyl CoA as an end product along with another acetyl CoA.
* cisΔ4-acyl CoA is oxidised by acyl CoA dehydrogenase to form transΔ2,cisΔ4-dienoyl CoA
* This is not a substrate for enoyl CoA hydratase
* 2,4 Dienoyl CoA reductase forms trans Δ3 enoyl CoA which still is not a substrate for Enoyl CoA hydratase
* CisΔ3-enoyl isomerase act to produce trans-Δ2-enoyl CoA which is a substrate
3-keotacyl CoA produces Propionyl CoA (if uneven amount of carbon) and Acetyl CoA in the thiolysis reaction catalysed by β-ketothiolase

Propionyl CoA is converted to succinyl CoA for entry into the citric acid cycle
Propionyl CoA - D-methylmalonyl CoA - L-methylmalonyl CoA - Succinyl CoA

Question 6

How is fatty acid oxidation regulated?

Answer 6

Carnitine acyl transferase I (Malonyl CoA (fatty acid synthesis) inhibits)
Hormone sensitive lipase
Energy status also has a role in regulation