fatty acid oxidation...fatty acid oxidation •provides energy to muscles from lipid stores, spares...
TRANSCRIPT
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Fatty acid oxidation Naomi Rankin
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Fatty acid oxidation
• Provides energy to muscles from lipid stores, spares glucose for the brain
• Lipolysis of triglycerides results in FFA, mainly C16 and C18
• FA oxidation provides lots of energy
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THE PATHWAY OF FATTY ACID OXIDATION AKA BETA-OXIDATION
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Part 1 – activation and transport
Acetyl CoA synthetase (ER or outer mitochondrial membrane)
CPT I
CPT II
Translocase
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• Carnitine AKA -hydroxy -trimethyl aminobutyric acid
• Enzymes are inside the inner membrane of the mitochondria/mitochondrial matrix
• Impermeable to CoA and fatty acyl CoA
• Carnitine caries fatty acyl CoA across the membrane
carnitine
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Carnitine transport
• CPT1 – transfers acyl group to carnitine
• Carnitine-acylcarnitine antiporter translocase
• CPT2 – fatty acyl group back to CoA
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Part 2 – oxidation
Acyl-CoA dehydrogenase
Hydroxyacyl-CoA dehydrogenase
Enol-CoA hydratase
-ketoacyl CoA thiolase
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-oxidation enzymes
• Acyl-CoA dehydrogenase – VLCAD C-12 to C-24
– LCAD branched chain FA
– MCAD C8-C10
– SCAD C4>C6>C8
• Enol CoA hydratase, hydroxyacyl-CoA dehydrogenase and thiolase – membrane bound tri-functional protein for LCFA but soluble matrix proteins for other FAs
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-oxidation control
• Availability of substrates and co-factors
• Availability of acetyl CoA most important
• Lots of glucose – acetyl CoA converted to malonyl CoA and fed into FA synthesis
• Low malonyl COA, a result of fasting, up-regulates CPT1 activity
• Rate limiting step for entry into mitochondria
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-oxidation energetics
• Each cycle produces – 1 acetyl CoA 10 ATP via TCA cylcle – 1 FADH2 1.5 ATP by ETC – 1 NADH 2.5 ATP by ETC
• Palmitoyl CoA C16 – 7 cycles – 8 acetyl CoA 80 ATP – 7 FADH2 10.5 ATP – 7 NADH 17.5 – Minus 2 ATP to adenylate the FA – 106 ATP per mole by complete oxidation
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Fatty acid utilization
• Depends on tissue – skeletal and cardiac muscle utilize FAs as a major energy source, the nervous system does not – it relies on glucose
• During prolonged fasting most tissues can use FA or ketones for E
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DISCOVERY
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Discovery
• Mainly through discovery of genetic defects
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IMPORTANCE IN HUMANS
Defects in Fatty acyl transport
Defects in -oxidation
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Carnitine palmitoyltransferase deficiency II
• CPTII mutation resulting in partial enzyme activity
• Muscle weakness – exercise intolerance
• Myoglubinurea
• Severe CPTII deficiency (>90%) presents in neonates – hypoketotic hypoglycaemia, hyperammonemia, cardiac malfunction and death
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CPT1 deficiency
• Rarer
• Possibly lethal and undiagnosed
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Carnitine-acylcarnine translocase deficincy
• Case described in 1992
• Died age 3
• 7ral similar cases since
• Hypoglycaemic coma
• Hyperammonemia
• Muscle weakness
• cardiomyopathy
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Treatment for all CPT deficiencies
• Avoid starvation
• Diet low in LCFA
• Supplement diet with MCFA
• Carnitine available orally for carnitine deficies caused by reduced activity of plasma membrane carnitine trasporter
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DEFECTS IN BETA-OXIDATION – ACYL-COA DEHYDROGENASE DEFICIENCIES
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Acyl CoA dehydrogenase deficiencies
• VLCADD
• LCADD
• MCADD 1/10,000 births
• SCADD
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Symptoms
• Lethargy, nausea, vomiting
• Acidosis, hyperammonaemia
• Hypoketotic hypoglycaemia
• Encephalopathy/cerebral oedema
• Hepatomegaly, fatty liver
• Seizures
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Treatment
• Avoid fasting
• If ill – give high calorie supplement or IV 10% dextrose if not tolerated
• Uncooked corn starch
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MCADD
• Part of new born screening program
• Peak age at presentation 12-18 months
• 25% die during 1st attack
• Preventable and treatable
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MCADD Case 1
• Child diagnosed with MCADD
• Patents told if child gets ill give them sugary drinks so don’t get hypoglycaemia
• Gave him sugar free Ribena
• Parents now get emergency packs containing sugary drinks and information on why to contact A&E
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MCADD Case 2
• 16 year old girl
• Got very drunk
• Vomiting for 2 days
• Admitted to ICU – acute encephalopathy and decompensation
• MCADD detected
• Treated and discharged
• Well since
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DETECTION
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Mass spectrometry at Glasgow
• ? Need to buy in some standards
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MNR
• Fatty acids detectable by NMR of native serum
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Conclusion
• Fatty acid oxidation – an important pathway for energy production
• Feeds into the citric acid cycle
• Important in human disease