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Fatty Acid Oxidation
Biochem and medical genetics
| Question | Answer |
|---|---|
| Role of Hormones | Signal to metabolism a fed state, substrate deficiency or fight or flight Metabolism responds by taking substrate up into tissues, returning substrate to the blood and diverting substrate into energy producing pathways |
| Insulin | Secreted by beta cells in the fed state Stimulated by increased blood glucose, certain amino acids and fatty acids Signal of substrate excess Tells tissue to store fuel and breakdown glucose |
| Glucagon | Secreted by alpha cells in the fasted state Stimulated by low glucose Signal of substrate deficiency Only acts on liver Signal to liberate glucose into blood from liver |
| Adrenaline | Secreted by the adrenal gland Fight or flight response Tell tissues to divert substrates towards making ATP |
| What are lipids | Diverse group of molecules Stored as triglycerides Used for energy as non-esterified fatty acids Converted into sterols and phospholipids Hydrophobic - need specialised transport molecules |
| Function of lipids in energy production | Large stores More energy dense per molecule than glucose Rapidly mobilised and stored Ideal for tissues with high energy demand Cant be used by all tissues Requires more oxygen than glucose |
| Processes involving fats | Digestion of dietary fats De novo lipogenesis Use in oxidative tissue to make energy Storage in adipose tissue Used to make ketone bodies in the liver |
| Digestions | Large triglycerides are hydrophobic and cannot move into cells Broken down by bile salts into smaller droplets Attacked by pancreatic lipases which break down TAG to generate NEFA and glycerol Makes mixed micelles which can be absorbed |
| Packaging into chylomicrons | Inside intestinal cells, mixed micelles are reformed into TAG Fatty acids are combined with cholesterol and glycerol to form chylomicrons These are surrounded by apoproteins to make them hydrophilic |
| Release of NEFA by lipoprotein lipase | LPL sits on surface of endothelial cells Hydrolyses TAG in the chylomicron into NEFA This releases NEFA for uptake by adipose and muscle LPL is activated by insulin |
| Adipose tissue | Organelles squashed to the outside Majority is a lipid droplet Adipose triglyceride is a mixture of saturated and unsaturated fatty acids |
| Transport of NEFA in the blood | NEFA is re-esterified into TAG to be stored NEFA is remobilised by lipase enzymes - Adipose triglyceride lipase, hormone sensitive lipase and monoacylglycerol lipase Hydrophobic NEFA transported in blood bound to albumin protein |
| Regulation of Hormone sensitive lipases | Activate by phosphorylation via adrenaline activating cAMP and PKA This increases fuel to the muscles and heart Inactivated by dephosphorylation by protein phosphatase, activated by insulin signalling |
| Plasma NEFA concentrations | Fed state - 0.3-0.6 mmol/L Prolonged exercise - 2 mmol/L Stress - 0.8-1.8 mmol/L Fasting - 0.5-2 mmol/L Thyroxine - 0.6-0.8 mmol/L |
| Storage in non-adipose tissue | Many cells have TAG stores Provides a source of energy is need to suddenly produce ATP TAG stores must be kept low to avoid damaging normal function Too much TAG leads to non-alcoholic fatty liver disease etc |
| Fatty acid metabolism in the heart | Fats are more energy rich than glucose - the heart needs more ATP per gram than any other organ Its use of TAG leaves glucose for cells which must use it 60-70% of ATP comes from fatty acid oxidation Contains intrinsic TAG stores |
| Fatty acid metabolism in the renal cortex | Kidneys require large amounts of energy to accomplish reabsorption Cortex is highly reliant on fatty acids Medulla has a poor oxygen supply - limited mitochondrial respiration so rely on glucose |
| Skeletal muscle and metabolism | Type 1 - slow twitch - oxidative - higher reliance on fatty acids Type 2 - slower fast twitch and faster fast twitch - glycolytic - rely on glucose In exercise initially use glycogen stores, then switch to fatty acids when these run out |
| Steps of fatty acid oxidation | Uptake Activation Carnitine shuffle Beta oxidation |
| Transport across the plasma membrane | Can diffuse across the membrane by a flip flop mechanism Transporter mediated uptake by fatty acid translocase - regulates uptake Intercellular FA is bound to cytoplasmic fatty acid binding protein |
| Activation | Fatty acids are activated in the cytosol by adding a CoA molecule to form Fatty acyl CoA Catalysed by Acetyl CoA synthetase Uses ATP Traps them in the cell and makes them a substrate for further enzymes |
| Transport into mitochondria | Need to cross highly impermeable inner membrane - no transporter Conjugated with carnitine which can be transported Achieved by 2 enzymes and one transporter |
| Carnitine Shuffle | Fatty acyl CoA conjugated with carnitine to form fatty acyl carnitine by CPT1 This crosses the membrane in CAT Fatty acyl carnitine is then converted back to fatty acyl CoA |
| Stages of beta oxidation | Oxidation of FACoA to trans enoyl Coa Hydration to Hydroxyacyl CoA dehydrogenase Oxidation to ketoacyl CoA thiolase Thiolysis to FACoA and Acetyl CoA |
| Isoforms of Acyl CoA dehydrogenase | Each breaks down different lengths of fatty acyl CoA Very long chain Long chain Medium chain Short chain |
| Products of Beta oxidation | Multiple acetyl CoA units Multiple NADH Multiple FADH2 There will be half the acetyl CoA as carbons in the FA e.g. 8 in a 16 C FA These feed into krebs cycle and oxidative phosphorylation |
| Dealing with unsaturated fatty acids | Contain a cis double bond Isomerase converts cis to trans double bond Reductase makes it a substrate for ongoing oxidation |
| Dealing with fatty acids with an odd number of carbons | B oxidation produces acetyl CoA with 2 carbons, so if an odd chain FA enters this is not possible The last cycle generates 1 Acetyl CoA and 1 propionyl CoA This can then be metabolised to succinyl CoA and enter the krebs cycle |
| Dealing with short chain fatty acids | Less than 6 carbons Enter mitochondria directly Bypass the carnitine shuffle |
| Dealing with very long chain fatty acids | 20-22 carbons Must be shortened in the peroxisomes to 16-18 carbons Then transferred to mitochondria This does not generate ATP but produces H2O2 |
| Dealing with branched chain fatty acids | Starts in peroxisomes with alpha oxidation before transfer to mitochondria for beta oxidation |
| Regulation of beta oxidation | Hormone sensitive lipase - regulated by hormonal phosphorylation as an external signal The carnitine shuffle - regulated intracellularly via allosteric control - inhibited by malonyl CoA from lipogenesis to prevent futile cycling |
| Systemic Carnitine deficiency | Relatively rare genetic disorder Unable to take carnitine up into cells, shutting down the carnitine shuffle Cardiomyopathy, fatty infiltration of organs, muscle weakness and hypoglycaemia Caused by switch from FAs to glucose as a fuel |
| Jamaican Vomiting Sickness | Poisoning - inhibition of Acyl CoA dehydrogenase Hypoglycin A is metabolised into a product that inhibits the first step of beta oxidation The body switches to using glucose Hypoglycaemia, coma and death |
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