Lipid Synthesis And Oxidation Flashcards
What are the main fatty acid derivatives?
- Fatty acids (fuel molecules)
- TAGs (fuel storage and insulation in adipose)
- Phospholipids (synthesis of membranes and lipoproteins)
- Eicosanoids (local mediators)
What are the main HMG derivatives?
- Ketone bodies
- Cholesterol (membranes and steroid hormone synthesis)
- Cholesterol esters (cholesterol storage)
- Bile acids and salts (lipid digestion)
What essential vitamins are fat soluble?
A, D, E and K
How are dietary lipids broken down to TAGs?
PANCREATIC LIPASE and BILE SALTS in the small intestine
How is glycerol metabolised?
- Converted to Glycerol Phosphate using GLYCEROL KINASE in the liver
- Oxidised to Dihydroxyacetone phosphate (DHAP) which is converted to Glyceraldehyde-3-P and enters step 5 of glycolysis
- Can also be used for TAG synthesis
Where does oxidation of fatty acids occur?
Mitochondrial matrix of hepatocytes
Why does the transport of fatty acids into the matrix of mitochondria require a specific mechanism?
Inner membrane of mitochondria is impermeable
Describe the function of the carnitine shuttle
- Transports fatty acids from the intermembrane space into the matrix
- Carnitine + Fatty acyl CoA —> Acyl Carnitine
- Acyl carnitine is shuttled across the membrane using CARNITINE ACYL TRANSFERASE
- Acyl Carnitine is converted back to Carnitine and Fatty Acyl CoA
Briefly describe how fatty acids are oxidised to produce acetyl CoA
- Fatty acids undergo β oxidation whereby a 2C unit is removed from the chain - ACETATE
- The acetate is combined with CoA to produce Acetyl CoA
- The shortened fatty acid then re-enters the cycle and is oxidised further
Why is there more energy derived from fatty acid oxidation than glucose oxidation?
- Fatty acids contain a large number of H atoms, therefore have a very high reducing power
- During oxidation of fatty acids, the H atoms are transferred to NAD+ and FAD+ to produce NADH and FADH2 which can be used in oxidative phosphorylation to produce ATP
Why are some polyunsaturated fats considered essential?
Body cannot synthesise polyunsaturated fats that contain more than 9 C=C bonds as it is unable to add a double bond past C9
Why can fatty acid oxidation not occur in the absence of oxygen?
- There is a set amount of NAD+ and FAD+ within the cell
- NADH and FADH2 produced in β oxidation must be reoxidised during oxidative phosphorylation in order for the process to continue
Why is acetyl CoA diverted from the KREBS cycle when the rate of fatty acid oxidation is high?
- Increased NADH and FADH2 produced which are high energy signals
- Inhibition of key regulatory enzymes in KREBS cycle such as Isocitrate dehydrogenase and α-ketoglutarate dehydrogenase therefore KREBS cycle stops
- Acetyl CoA cannot enter KREBS cycle so is diverted to an alternative pathway called KETOGENESIS in order to produce energy
Why are ketone bodies produced when glucose is low?
- Low glucose levels stimulate the release of glucagon and cortisol (stress response)
- Glucagon inhibits cholesterol synthesis by inhibiting HMG CoA reductase and activates ketogenesis by activating Lyase
- Lyase converts HMG CoA into Acetoacetate, which is then converted to other ketones
How are ketones metabolised to produce energy?
- Ketones are produced in the liver and are water soluble
- Acetoacetate and β-hydroxybutyrate are transported in the blood to muscle tissues where they are reoxidised to Acetyl CoA (which enters KREBS)
- Acetone (produced by the spontaneous breakdown of Acetoacetate) is volatile and is excreted via the lungs
How does the Carnitine shuttle regulate the oxidation of fatty acids?
- Controls the entry of fatty acids into the matrix
- Malonyl CoA (an intermediate of fatty acid synthesis) inhibits Carnitine Acyl Transferase thereby inhibiting the metabolism of newly synthesised fatty acids
Explain why defects in the Carnitine shuttle may lead to exercise intolerance
- Fatty acids a cannot enter the mitochondrial matrix to be oxidised
- As a result, fatty acids accumulate in muscles and lipid droplets form, causing muscle weakness and exercise intolerance
How is ketogenesis controlled?
- HORMONALLY
- Activated in stress situations by glucagon, cortisol, adrenaline, growth hormone and thyroxine
- INHIBITED BY INSULIN
Why are ketones essential during starvation?
Provide an alternative energy source for muscle so glucose can be conserved for those tissues which have an absolute requirement e.g. Brain, RBC
Explain the action of statins drugs and why they are used to treat people which high cholesterol
- Inhibit cholesterol synthesis by inhibiting HMG CoA reductase
- Decreased cholesterol produced therefore cholesterol levels are lowered
How is the metabolism of TAGs controlled?
- HORMONALLY
- Broken down into fatty acids by HORMONE SENSITIVE LIPASE
- Inhibited by INSULIN
- Promoted by GLUCAGON, CORTISOL, ADRENALINE, THYROXINE and GROWTH HORMONE
What vitamin is essential for fatty acid oxidation and why?
- B5 pantoethanic acid
- Required for the synthesis of Coenzyme A
- All intermediate molecules of fatty acid oxidation are linked to and activated by CoA
Explain how prolonged starvation may lead to ketoacidosis
- Starvation stimulates stress response and release of glucagon and cortisol which promote fatty acid oxidation
- Increased fatty acid oxidation and production of ketone bodies (increased activity of Lyase)
- Accumulation of ketones in blood as they are being transported from liver to muscle tissues
- Acetoacetate and β-hydroxybutyrate are strong acids so cause an increase in H+ in blood
- Alteration of the buffering capacity of the blood leading to decreased pH and acidosis
What are the signs of ketoacidosis?
- Hyperventilation and Kussmaul breathing
- Prostration
- Nausea
- Vomiting
What is ketouria?
Excretion of ketones in the urine due to increased plasma concentrations above the renal threshold
Why are TAGs stored in an anhydrous form?
They are HYDROPHOBIC so must be stored in the absence of water (in ADIPOSE TISSUE)
Why does fatty acid synthesis occur mainly in the liver?
Dietary glucose is a major source of carbon
Why is it increasingly difficult for obese people to lose weight?
As there is an increase in dietary fats, the adipocytes undergo cell growth (hypertrophy) and increase in number (hyperplasia), therefore there is an increase in fat stores so take much longer to break down
What two cofactors are needed for the synthesis of fatty acids?
- ATP
- NADPH
What is the main complex responsible for the synthesis of fatty acids?
Fatty Acid Synthase Complex
What is the main substrate for fatty acid synthesis?
Malonyl CoA
What is the role of citrate in lipogenesis?
- Inner membrane is impermeable to acetyl CoA
- Citrate formed in liver mitochondria from acetyl CoA and oxaloacetate
- Transported out of the mitochondria into the cytoplasm where it is cleaved into acetyl CoA and oxaloacetate
- ALLOWS THE TRANSFER OF ACETYL COA FROM MITOCHONDRIA TO CYTOPLASM
What is the key regulatory enzyme in lipogenesis?
Acetyl CoA Carboxylase
How is the activity of acetyl CoA carboxylase controlled?
- ALLOSTERICALLY by citrate and AMP
- COVALENT MODIFICATION by insulin and glucagon/adrenaline
- Insulin promotes the dephosphorylation thereby activating the enzyme
What are the main sources of NADPH for lipid synthesis?
- Pentose phosphate pathway
- Malate –> Pyruvate
What is the fate of fatty acids synthesised in the liver?
Transported via CLDL to ADIPOSE for storage or MUSCLE for energy production
How much of a healthy 70kg man should be fat?
~15kg
