L15 - fatty acid oxidation Flashcards
Fatty acid catabolism: how many steps are there and what happens in each step?
Step one of fatty acid catabolism: what is it and what happens in it?
Release of fatty acids from TAG
Endogenous TAG stores/TAG carried around in lipoproteins are broken down by lipases, releasing fatty acids (ATGL, HSL, MGL, LPL, etc)
Step two of fatty acid catabolism: what is it and what happens in it?
Uptake of fatty acids
Fatty acid transporters move fatty acids across the plasma membrane into cells
FAT/CD36 regulate this by only moving to the membrane from vesicles when needed
Step three of fatty acid catabolism: what is it and what happens in it?
Movement into the mitochondria
- Converted to acyl-CoA - this is the activation step and it uses 2 ATP equivalents
- Short fatty acids (<12C) can simply diffuse across the membranes but longer chains require the carnitine shuttle
Similar process for TAG synthesis (?)
This is the most regulated step
Step four of fatty acid catabolism: what is it and what happens in it?
beta-oxidation of fatty acids
- Stage 1 - fatty acid chain sequentially oxidised to produce 2 carbon acetyl-CoA units plus NADH and FADH2
- Stage 2 - oxidation of acetyl-CoA into CO2 via citric acid cycle with concomitant generation NADH and FADH2
- Stage 3 - generates ATP from NADH and FADH2 via the respiratory chain
Carnitine shuttle: what is it, what is the mechanism behind it, what is it regulated by, and what clinical implications are involved in its deficiency?
Transport system allowing movement across the mitochondrial membrane using carnitine
- Carnitine acyltransferase 1 transfers the acyl group from acyl-CoA to carnitine which can then pass through the membrane using a transporter
- Carnitine transferase 2 transfers the acyl group from the carnitine to a CoA enzyme, recycling carnitine to go back through the membrane to the cytosol to transfer another acyl group to the mitochondria
- The carnitine transporter is an antiport transporter, exchanging two carnitines across the membrane
Malonyl-CoA?
??
Fatty acid oxidation regulation: what types are there and what mechanisms are responsible for them?
- Release of FA from TAG - HSL/ATGL and LPL
- FA uptake - FA transport proteins - FAT/CD36
- Entry of FA into mitochondria - carnitine shuttle
Coordinated regulation of fatty acid oxidation and biosynthesis
leccy it up
When are malonyl CoA levels high?
When there are high carbohydrate levels - high levels, FA less needed for TCA(?)
Inverse occurs at low blood glucose levels - FA needed for TCA cycle (???)
Acetyl-CoA carboxylase isoforms
ACC1 - used in fatty acid synthesis, regulated by citrate (phosphorylation), high in lipogenic tissues, low in catabolic tissues, localised in the cytosol
ACC2 - regulates FA oxidation, regulated by citrate (phosphorylation), found in lipogenic and catabolic tissues, localised in the mitochondria
ACC2: what is it, what does it do, how is it regulated, and what clinical implications can it have?
Acetyl-CoA carboxylase - an enzyme located in the mitochondria that is found in lipogenic and catabolic tissues
Regulation of fatty acid oxidation by producing malonyl-CoA at the mitochondrial membrane - producing it causes ?? inhibition and results in FA transport into the mitochondria for oxidation
Regulated by citrate through phosphorylation
ACC2 knockout mice are resistant to diet induced obesity - potential drug target for obesity?
Ketone bodies: why are they an alternative route for fatty acid catabolism, what are the mechanisms behind it, where does it occur, and when is it used?
Entry of acetyl-CoA into the citric acid cycle requires oxaloacetate (OAA) - when it is depleted, Acetyl-CoA accumulates, which can then be converted into ketone bodies
- Three acetyl-CoAs are condensed to produce HMG-CoA,
- HMG-CoA is converted to acetoacetate in the mitochondria/used to synthesise cholesterol in the cytosol (this enters the bloodstream)
- Acetoacetate is broken down into acetone and beta-hydroxybutyrate
- Acetone is released in the breath and acetoacetate and beta-hydroxybutyrate are transported to extrahepatic tissues for energy production (ie brain)
Liver
- β oxidation of FA is high (lots of acetyl-CoA produced)
- Glucose availability/utilisation low (OAA levels fall)
- Conditions that promote gluconeogenesis: untreated diabetes, starvation
Ketone bodies: how useful are they as an energy source and ? ?
- They are water-soluble and able to move to extrahepatic organs
- Can be used by tissues that would usually oxidise glucose - enables these tissues to utilise lipid-derived fuel, sparing glucose
- Decreases the need for gluconeogenesis - sparing muscle protein
- Frees CoA from acetyl-CoA so fatty acid oxidation can continue
Liver does not contain CoA transferase
What tissues utilise ketone bodies as an energy source?
- Some tissues (heart) get much of their energy from ketone bodies
- Other tissues (brain) only use ketone bodies when glucose is not available
Diabtetic ketoacidosis
Untreated diabetes: lack of insulin/insulin resistance
↑ release of fatty acids from adipose tissue stores
↑ circulating FA
↑ β-oxidation
↑ Gluconeogenesis
OAA ↑ acetyl-CoA
↑ ketone body synthesis
Plasma concentration 25-30mM
Ketone bodies are acids (pKA~3.5) ⇒
Impairs ability of haemoglobin to bind oxygen
