10 - Lipid and Ketone Body Metabolism Flashcards
What is the general structure of a lipid?
- Diverse, contain C,H and O and sometimes P, N
- More reduced than carbohydrates
- Not water soluble
What are the three classes of lipids?
Fatty acid derivatives:
- FA = fuel molecule - TAG = storage molecule
- Phospholipids - Eicosanoids (local mediators)
Hydroxy-methylglutaric acid derivatives:
- Ketone bodies (C4 - water soluble)
- Cholesterol - Cholesterol esters (storage)
- Bile acid and salts
Vitamins:
A,D,E,K essential
How is TAG synthesised and broken down?
- Under hormonal control to be stored in adipose anhydrously as hydrophobic.
Esterification: Insulin
Lipolysis: Glucagon, Cortisol, Adrenaline, GH
Lipolysis during starvation, pregnancy and prolonged exercise
How are triacylglycerols metabolised extracellularly?
- Hydrolysed by pancreatic lipase in SI. Requires bile salts
- Produce FA and Glycerol
Where does B-oxidation not occur?
- RBC as no mitochondria
- Brain as FA can’t pass blood-brain barrier
What happens to glycerol when it has been produced from TAG metabolism?
Goes through blood to liver where it is stored or metabolised
What happens to FA when they have been digested from TAG?
- Converted back to TAG in G.I
- Packaged into lipoproteins called chylomicrons
- Released into circulation by lymphatics and carried to adipose tissue to be stored
- Released by hormone-sensitive lipase
- Carried to consumer tissues by albumin - FA complex
How are fatty acids held in adipose tissue?
- When glucose conc decreases, insufficient glycerol-1-phosphate so fatty acyl-coA cant be converted so FA builds up due to backlog and is released
What is B-oxidation?
Oxidation of fatty acids to release energy, in the mitochondria
What are the two properties of fatty acids?
- Amphipathic
- Saturated/Unsaturated (linolenic acid essential as can’t introduce C double bond after C9)
How are fatty acids catabolised?
- Activated by linking to CoA outside the mitochondria
- Transported via carnitine shuttle through inner mitochondrial membrane as activated FA do not readily cross inner membrane
- Series of oxidative reactions with C2 removed each time and NADH and FADH2 being produced each time
How are fatty acids activated?
Fatty acyl CoA synthase links FA to CoA, using ATP.
How does fatty-acyl CoA get across inner mitochondrial membrane?
- On it’s own cant get across membrane so CAT 1 (carnitine acyltransferase) removes CoA and adds carnitine to produce acyl carnitine
- Acyl carnitine shuttles across carnitine shuttle transporter into mitochondria
- CAT2 adds CoA back and removes carnitine which shuttles back over.
How is carnatine shuttle transporter regulated?
- Controls rate of FA oxidation
- CAT inhibited by biosynthetic intermediate malonyl CoA
- If dect in CAT, will lead to lipid droplets in abnormal places as lipids can’t be broken down
Explain key points of B-oxidation?
- Cycle removing 2C each time
- Oxidation
- Produces NADH and FADH2
- Needs O2
- No ATP synthesis
- Greater yield than glucose as more turns of TCA
Why is acetyl coA the convergance point of catabolic pathways?
- Acetyl (CH3CO) linked to CoA by S bond
- High energy when hydrolysed so acetyl is activated
- CoaA made of Vitamin B5
Why can’t glucose be made by reversing glycolysis of pyruvate?
Some irreversible reactions, have to bypass these steps using other routes
How is acetyl CoA produced and how does it synthesise lipids?
- Catabolism of FA, sugars, alcohol and AA
- In liver lipids synthesised. 2 CoA makes FA, 3 CoA makes HMG
What are the three main ketone bodies and their functions?
- Acetoacetate, B-Hydroxybutyrate, Acetone (breakdown of acetoacetate)
Used as an alternative fuel source to glucose in starvation. Acetone excreted
Where are ketone bodies produced and what are normal levels?
Ketone bodies are synthesised in liver mitochondria from acetyl~CoA by a pathway that produces hydroxymethyl glutaryl CoA (HMG CoA). This is converted to acetoacetate by a lyase enzyme These enzymes are regulated by hormones
- <1mM normal
- 2-10mM starvation
- >10mM untreated type 1 diabetes (fruit breath)
What is ketone body production regulated by?
Insulin to Glucagon ratio.
- Low ratio, lyase activated and reductase inhibited
- High ratio , reductase activated and lyase inhibited
What do statins do?
They inhibit the enzyme that converts HMG-CoA into cholesterol
Why are ketone bodies synthesised?
- Alternative source of energy during starvation to allow there to still be some glucose for cerebal activity
- Used by all tissues that contain mitochondria, even CNS
- Converted to CoA so can enter TCA
What is the general process of ketogenesis during early starvation?
- Low glucose
- FA released by lipolysis in adipose
- Travel to liver by blood
- Ketoneogenesis (as high NADH from fatty acids being converted to acetyl coA so signals inhibits TCA enzymes isocitrate dehydrogense and a-ketoglutarate dehydrogenase, so acetyl coA forced down ketone route)
- KB travel by blood to tissue and are utilised to form acetyl CoA
- Enter TCA
What is the process during late starvation?
- Adipose stores mobilised for keton bodies to supply energy for rest of body
- Proteins in muscle broken down to aa for gluconeogenesis in liver for glucose for brain
- Glycogenolysis in liver for basal glucose
Why can ketones travel in the blood?
They are water soluble
What is ketonuria?
Ketones in urine due to ketone body levels above renal threshhold
What is ketoacidosis?
- Ketone bodies are strong organic acids and are dissolved in blood. Large concentrations of them in the blood mean buffering system cant deal with them so lower pH
- Acetone can be excreted via lungs so can smell it on breath
- Likely to occur in untreated type 1 diabetes
What does ketogenesis rely on?
- Insulin:Glucagon plasma ratio
- Fatty acid substrate in liver from lipolysis in adipose
What is coenzyme A derived from?
Vitamin B5
Why do fatty acids release more energy than glucose?
The break down of lipids by beta-oxidation causes more acetyl CoA to be formed, e.g 9, so more turns of the TCA and more reducing power produced
How do ketone bodies join the TCA cycle?
Discuss all 4 stages of catabolism for protein, carbohydrates, lipids (TAGS) and alcohol.
