Oxidation of fat Flashcards
How is fat stored
Stored as triacylglycerols (also called neutral fats or triglycerides), which are uncharged esters of fatty acids with glycerol.
Storage is in adipocytes and (less healthily) in the liver
What proportion of dietary lipid is in the form of triacylglycerols?
90%
What is the advantage of using fats in metabolism?
They don’t require hydration
Adipose tissue storage unlimited
They are a highly reduced fuel
What is the function of lipases?
Converts triglycerides into glycerol and free fatty acids
What are free fatty acids bound to in transportation?
What is the purpose of this?
Albumin
Prevents damage to capillaries
What is the ‘safe’ conc of free fatty acids?
2mM
How long would adipose TAG supplies last in starvation?
34 days `
What is the function of hormone sensitive lipase?
converts TAG to DAG to MAG to FFA
What enzyme(s) converts TAG to DAG?
Adipose triglyceride lipase (ATGL) and hormone sensitive lipase (HSL)
What enzyme(s) converts DAG to MAG?
HSL
What enzyme(s) converts MAG to FFA?
HSL and MAGL
What is DAG?
Diacylglyceride
What is MAG?
Monoacylglyceride
How is HSL activated?
Phosphorylation catalysed by protein kinase A
cAMP raised by a number of hormones Including glucagon (liver not adipose), adrenaline and noradrenaline
What inhibits HSL?
Insulin activates phosphodiesterase to lower cAMP
What raises FFA levels?
Fasting, prolonged exercise, stress and strong black coffee
What mediates long term effects of hormonal HSL control?
Thyroxine and glucocorticoids
What happens to FFA released from
adipose tissue?
Taken up by liver and muscle, where
FFA inhibits glucose utilisation as fuel
Most goes to skeletal muscle and heart during sustained exercise
Where does β-oxidation occur?
Inner membrane of the mitochondria
What is β-oxidation?
A process whereby aliphatic fat is converted into aceyl CoA which can be used in the Kreb’s cycle
How is FFA prepared for β-ox?
Fatty acids cleaved from glycerol backbone activated using CoA to form acyl-CoA via fatty acid synthase
The formation of a high energy bond between CoA-SH and a fatty acid results in ATP being converted to AMP.
The overall reaction is made favourable because the PPi formed is hydrolysed to Pi
Why are there different acyl-CoA synthases?
For different chain-length fatty acids
What is the role of carnitine in β-ox?
Activation occurs at the outer mitochondrial membrane but the resulting fatty acyl-CoA cannot diffuse across the membrane
Carnitine transports fatty acid after modification by carnitine acyl-transferase I
Once inside the fatty acid is transferred back to CoASH in a reaction catalysed by carnitine acyltransferase II
What happens in the first oxidative stage of β-ox?
An activated fatty acid is oxidized to introduce a double bond
What happens in the hydration stage of β-ox?
The double bond is hydrated (addition of water) to introduce an oxygen
What happens in the second oxidative stage of β-ox?
The alcohol group is oxidized to a ketone
What happens in the thiolysis stage of β-ox?
Coenzyme A attacks at Cβ to yield acetyl-CoA and a fatty acid chain two carbons shorter
How is β-ox initiated in monounsaturated fats?
There is an isomerase which shifts the double bond so that it is on the normal oxidation pathway.
How is β-ox initiated in polyunsaturated fats?
One double bond is shifted in the same way and others are reduced to form standard saturated bonds
What is the purpose of β-oxidation
FADH2, NADH, and acetyl-CoA are all generated
Thus, we can generate ATP by oxidation in the citric acid cycle (for acetyl-CoA) and oxidative phosphorylation (for all the NADH and FADH2 generated)
How many reaction cycles are required for the degradation of palmitoyl CoA (C16-acyl CoA)
7
What is the stoichiometry of oxidation of palmitoyl CoA?
Palmitoyl-CoA + 7FAD + 7NAD+ + 7CoA + 7H2O ——> 8acetyl-CoA + 7FADH2 + 7NADH + 7H+
How much ATP is generated from the degradation of palmitoyl CoA?
106
7NADH
7FADH2
8 acetyl CoA (each citric acid yields 10)
2 ATP used in activation of palmitate
What does the fetal heart metabolism rely on?
When are fatty acids first used in metabolism?
Glucose
After birth
How many FAD-dependent acyl-CoA dehydrogenases are there?
4
What are the FAD-dependent acyl-CoA dehydrogenases?
- Very Long chain acyl CoA dehydrogenase or VLCDH (C12-C24)
- Long-chain or LCDH (C8-C20)
- Medium chain or MCDH (C4-C12)
- Short chain or SCAD (C4-C6)
What is MCAD deficiency?
Babies cannot oxidise fatty acids so readily, and die during the night when glycogen is depleted
What proportion of cot death is due to MCAD deficiency?
10%
What type of fruit produces sickness due to its role in β-ox?
Unripe ackee fruit causes Jamaican vomiting sickness
Contains inhibitor of acyl-CoA dehydrogenases which depletes glycogen reserves
What happens to most acetyl CoA in the liver?
Not oxidised, instead it is converted into ketone bodies and exported for use by muscle (especially heart) and brain
What are the 3 ketone bodies?
Acetoacetate
β-hydroxybutyrate
Acetone
Which ketone body is exhaled on the breath?
Acetone
What is meant by ‘fats burn in the flame of carbohydrates’
Fatty acid oxidation is incomplete if citric acid cycle intermediates are being drained to make glucose
What enzyme to statins target?
HMG-CoA reductase in the cytosol to block cholesterol biosynthesis
What is HMG-CoA?
Liver precursor for de novo synthesis of cholesterol
Why does the brain use ketone bodies rather than FFAs when glucose is low?
Ketone bodies can cross the blood-brain barrier (unlike FFA )
Soluble, don’t need albumin for transport
Can glucose be produced from fat?
What is the exception to this?
No
Glycerol produced from TAGs can be recycled. Since adipose tissue does not have glycerol kinase the glycerol must be circulated to the liver
What are the 4 mechanisms for the regulation of b-oxidation?
- Lipolysis of TAG
- Re-esterification of fatty acids
- Transport into mitochondria
- Availability of NAD+ and FAD
How is fatty oxidation regulated by re-esterification
GPATs (re-esterification enzymes) are inhibited by cAMP-PKA phosphorylation/stimulated by insulin
During fasting the concentration of insulin is low
GluT4 is not recruited in adipose cells
Little glucose uptake
and Glycerol 3-phosphate is low
These changes prevent free fatty acids (as CoA
derivs) from re-esterification
Fatty acids are released to circulate to other tissues
How is fatty oxidation regulated by transport into mitochondria?
The carnitine shuttle is inhibited at CAT-I by malonyl-CoA in liver
Malonyl-CoA is produced during fatty acid synthesis
Prevents synthesis and degradation occurring alongside each other in liver
Where in the body does malonyl CoA act as a regulatory molecule?
Liver and muscle
How is fatty oxidation regulated by the availability of NAD+ and FAD?
There is competition with the citric acid cycle for these co-factors, which can limit activity
What is the function of peroxisomes?
Mitochondria cannot import very long chain fatty acids (>22 carbons)
Long fatty acids are oxidised in peroxisomes which chew up fats for synthesis purposes and to supply the mitochondria with shorter chain fatty acids
How can PPARs be used for treating type II diabetes and obesity
PPARα in the liver promotes transcription of genes for FFA use, target for fibrate drugs against hypertriglyceridaemia (risk of coronary heart disease)
PPARγ controls adipogenesis, improves insulin sensitivity, target for thiazolidinediones
PPARδ (or β/δ) is expressed ubiquitously, its activation may combat multiple components of the metabolic syndrome
What are PPARs?
Peroxisomal Proliferation Activated Receptors
Ligand inducible transcription factors which
regulate energy metabolism by acting as nutritional sensors
Their natural ligands are lipids or lipid-related (but largely unidentified)
