Fats- Lipolysis and Beta Oxidation Flashcards
What are fats composed of?
Carbon, hydrogen and oxygen
What is triacylglycerol?
- Fats and oils
- 1 glycerol and 3 fatty acid tails
- Vary in length and location of double bonds in tails
Where do you find the omega carbon on a fatty acid?
At the methyl end
- Last carbon on the outside portion of the fatty acid
Where do you find the alpha carbon on a fatty acid chain?
At the carboxyl end of the chain
How are fatty acids named?
- By the number of carbons in the chain and number and location of C=C double bonds
- E.g. omega-3 fatty acids represent that the double bond is 3 carbons away from the omega carbon
What happens to fatty acids in the basal state?
- A few hours after a meal
- During fasting, fatty acids released from adipose tissue after undergoing lipolysis
What is lipolysis?
Breakdown of triglycerides into fatty acids and glycerol
What happens to glycerol after lipolysis in the basal state?
- Travels to liver and its carbons used for gluconeogenesis
What happens to fatty acids after lipolysis in the basal state?
- Go to tissues requiring energy
- Converted to acetyl coA
- Muscle–> acetyl CoA enters TCA cycle
- Liver–> Acetyl CoA converted to ketone bodies and delivered to the blood
What molecule do fatty acids form complexes with and what happens to them?
- Albumin
- Taken up by muscles, kidneys and other tissues
- Complete oxidation to produce CO2, water and ATP (via beta-oxidation, TCA and electron transfer chain)
- Partially oxidised in liver to form ketone bodies
- Ketone bodies released in blood for uptake by other tissues to convert to acetyl CoA
What is the signal transduction pathway leads to lipolysis?
- Glucagon/Adrenalin –> Adenylyl cyclase –> cAMP –> protein kinase A (PKA)
- PKA activates hormone sensitive lipase (HSL)
What hormone deactivates HSL?
Insulin
What might be generated from beta oxidation?
- Some ATP generated through reduction electron carriers
- Acetyl CoA (used to make ketone bodies)
Describe the metabolism of short chain fatty acids
- 2-4 carbons
- Site of catabolism- mitochondrion
- Membrane transport- diffusion
Describe the metabolism of medium chain fatty acids
- 4-12 carbons
- Site of catabolism- mitochondrion
- Membrane transport- diffusion
Describe the metabolism of long chain fatty acids
- 12-20 carbons
- Site of catabolism- mitochondrion
- Membrane transport- carnitine cycle
Describe the metabolism of very-long chain fatty acids
- Site of catabolism- peroxisome
- First shortened to long chains in the peroxisome
How are fatty acids activated?
- Prior to oxidation, fatty acids are activated by a reaction that creates a thirster linkage to CoA
What is the enzyme that catalyses the two-step process that forms fatty acyl CoA?
Fatty acid thiokinase
What are the reactions that take place to form Acyl CoA from fatty acids?
- Fatty acid + ATP –> Acyl adenylate + PPi
(oxygen replaced with AMP) - Acyl adenylate + HS-CoA –> Acyl CoA + AMP
Why is the carnitine shuttle required?
- CoA is a large polar molecule derivative which cannot penetrate the inner mitochondrial membrane
Describe the carnitine shuttle
- CPT1 in the outer mitochondrial matrix swaps CoA bound to fatty acyl for carnitine
- Enzyme transports fatty acyl carnitine into mitochondrial matrix
- CPT-2 swaps carnitine back for CoA
- Fatty acyl CoA is in matrix and free carnitine is pumped back into inter-membrane space
What is CPT-1 and 2?
Carnitine palmitoyl transferase-1 and 2
What enzyme transports fatty acyl carnitine into mitochondrial matrix?
Carnitine acyl carnitine translocase
What is the first oxidation step of beta oxidation?
- Activated fatty acid
- Enzyme Acyl CoA dehydrogenase
- FAD –> FADH2
- Forms Acyl- CoA
Describe the hydration step of beta oxidation
- Addition of water
- Hydratase enzyme
Describe the 2nd oxidation step of beta oxidation
- Hydroxy acyl CoA dehydrogenase enzyme
- NAD+ –> NADH H+
- Beta carbon is oxidised to a ketone and electrons are transferred to NAD+
Describe cleavage step of beta oxidation
- Thiolase enzyme
- Addition of CoA
- Cleavage of last 2 carbons with CoA attached. (2 carbon = acetyl CoA)
Produces Acetyl CoA that can enter TCA cycle - Remaining chain undergoes beta oxidation again until all used up
How is beta oxidation different in unsaturated fatty acids?
- Already partially oxidised and so produces less FADH2 , so less ATP, requires additional enzymes both to manipulate double bonds
How is beta oxidation different in odd chain fatty acids?
- Oxidation proceeds in the same way until final round of degradation
- 3-carbon propionyl CoA is formed by last thiolase cleavage reaction
- Propionyl converted to succinyl-CoA by a separate pathway and the enters TCA cycle
How do branched chain fatty acids undergo beta oxidation?
- An enzyme (acyl CoA Alpha-hydroxylase) will cleave a carbon dioxide and the chain left undergoes beta-oxidation.
What is Adult Refsum Disease?
- Type of leukodystrophies, which damage white matter if brain and affect motor movements
- Autosomal recessive deficiency of PHYH needed for phytanic acid metabolism
- Toxic levels of phytanic acid build up in brain, blood and other tissues
What are the consequences of high levels of phytanic acid in ARD?
- Late childhood onset with nigh blindness due to retinitis pigments and anosmia
- deafness, ataxia, peripheral neuropathy, ichthyosis and cardiac arrythmias
- Shortened bones in fingers and toes
What is the treatment for ARD?
Avoid foods that contain phytanic acid- plasma exchange
What are Peroxisome Biogenesis Disorders?
- 3 autosomal recessive inherited disorders
- Mutations in any of 13 PEX genes that encode peroxins- proteins necessary to make peroxisomes
- Very long chain fatty acids are shortened to long chains in peroxisome
How does peroxisome biogenesis disorder affect plasma concentration of VLCFA?
- Elevated concentration of very long chain fatty acid
- Indicates defects in peroxisomal fatty acid metabolism
What are the three peroxisome biogenesis disorders?
- Zellweger syndrome
- Neonatal adrenoleukodystrophy
- infantile refuse disease
What can brain disorders result in?
- Skeletal and craniofacial dysmorphism
- Liver dysfunction
- Progressive sensorineural hearing loss
- Retinopathy
Which peroxisome biogenesis disorder is the most severe?
Zellweger syndrome
- Most infants do not survive past 1st 6 months
- Death from respiratory distress, GI bleeding or liver failure
What is Medium-Chain Acyl CoA Dehydrogenase deficiency (MCAD)?
- Recessive deficiency of medium chain acyl-CoA dehydrogenase, most common genetic disease relating to fatty acid metabolism
- Linked to sudden infant death
What is MCAD characterised by?
- Hyoketotic hypoglycaemia
- In response to fasting or metabolic stress (e.g. illness)
- Body unable to metabolise fat (so no ketones produced)
- Continues to metabolise glucose producing hypoglycaemia
How does MCAD present?
- Infants older than three months when overnight feeding reduced
- Gap between feeds long enough for acute hypoglycaemia to occur
- Produces symptoms of preprandial irritability, drowsiness, jitteriness, sweating, coma and seizures
What is the treatment for MCAD?
Avioid fasting
