Fatty Acid Metabolism
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Transcript of Fatty Acid Metabolism
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Fatty Acid Metabolism
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Introduction of Clinical Case
10 m.o. girl – Overnight fast, morning seizures & coma– [glu] = 20mg/dl– iv glucose, improves rapidly
Family hx– Sister hospitalized with hypoglycemia at 8
and 15 mo., died at 18 mo after 15 hr fast
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Introduction of Clinical Case
Lab values– RBC count, urea, bicarbonate, lactate, pyruvate, alanine,
ammonia all WNL– Urinalysis normal (no organic acids)
Monitored fast in hospital– @ 16 hr, [glu]=19mg/dl– No response to intramuscular glucagon– [KB] unchanged during fast– Liver biopsy, normal mitochondria, large accumulation of
extramitochondrial fat• [carnitine normal]• Carnitine acyltransferase activity undetectable
– Given oral MCT• [glu] = 140mg/dl (from 23mg/dl)• [Acetoacetate] = 86mg/dl (from 3mg/dl), similar for B-OH-
butyrate Discharged with recommendation of 8 meals per day
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Overview of Fatty Acid Metabolism: Insulin Effectsfigure 20-1
Liver– increased fatty acid
synthesis• glycolysis, PDH, FA
synthesis
– increased TG synthesis and transport as VLDL
Adipose– increased VLDL
metabolism• lipoprotein lipase
– increased storage of lipid
• glycolysis
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Overview of Fatty Acid Metabolism: Glucagon/Epinephrine Effectsfigure 20-2
Adipose– increased TG
mobilization• hormone-
sensitive lipase
Increased FA oxidation– all tissues
except CNS and RBC
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Fatty Acid Synthesisfigure 20-3
Glycolysis– cytoplasmic
PDH– mitochondrial
FA synthesis– cytoplasmic– Citrate Shuttle
• moves AcCoA to cytoplasm
• produces 50% NADPH via malic enzyme
• Pyruvate malate cycle
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Fatty Acid Synthesis Pathway
Acetyl CoA Carboxylase
‘first reaction’ of fatty acid synthesis AcCoA + ATP + CO2 malonyl-CoA + ADP + Pi
malonyl-CoA serves as activated donor of acetyl groups in FA synthesis
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Fatty Acid Synthesis Pathway
FA Synthase Complexfigure 20-4
Priming reactions– transacetylases
(1) condensation rxn
(2) reduction rxn (3) dehydration rxn (4) reduction rxn
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Regulation of FA synthesis: Acetyl CoA Carboxylase Allosteric regulation stimulated by citrate
– feed forward activation inhibited by palmitoyl CoA
– hi B-oxidation (fasted state)– or esterification to TG limiting
Inducible enzyme– Induced by insulin– Repressed by glucagon
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Regulation of FA synthesis: Acetyl CoA Carboxylasefigure 20-5
Covalent Regulation
Activation (fed state)– insulin induces protein
phosphatase– activates ACC
Inactivation (starved state)– glucagon increases
cAMP– activates protein kinase A– inactivates ACC
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Lipid Metabolism in Fat Cells:Fed Statefigure 20-6
Insulin stimulates LPL
– increased uptake of FA from chylomicrons and VLDL
stimulates glycolysis– increased glycerol
phosphate synthesis
– increases esterification induces HSL-
phosphatase– inactivates HSL
net effect: TG storage
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Lipid Metabolism in Fat Cells:Starved or Exercising Statefigure 20-6 Glucagon,
epinephrine activates adenylate
cyclase– increases cAMP– activates protein kinase
A– activates HSL
net effect: TG mobilization and increased FFA
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Oxidation of Fatty AcidsThe Carnitine Shuttlefigure 20.7
B-oxidation in mitochondria IMM impermeable to FA-CoA transport of FA across IMM requires the carnitine
shuttle
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B-Oxidationfigure 20-8
FAD-dependent dehydrogenation
hydration NAD-dependent
dehydrogenation cleavage
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Coordinate Regulation of Fatty Acid Oxidation and Fatty Acid Synthesis by Allosteric Effectorsfigure 20-9
Feeding– CAT-1 allosterically
inhibited by malonyl-CoA– ACC allosterically
activated by citrate– net effect: FA synthesis
Starvation– ACC inhibited by FA-CoA– no malonyl-CoA to inhibit
CAT-1– net effect: FA oxidation
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Hepatic Ketone Body Synthesisfigure 20-11
Occurs during starvation or prolonged exercise– result of elevated FFA
• high HSL activity
– High FFA exceeds liver energy needs
– KB are partially oxidized FA
• 7 kcal/g
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Utilization of Ketone Bodies by Extrahepatic Tissuesfigure 20-11
When [KB] = 1-3mM, then KB oxidation takes place– 3 days starvation [KB]=3mM– 3 weeks starvation
[KB]=7mM– brain succ-CoA-AcAc-CoA
transferase induced when [KB]=2-3mM
• Allows the brain to utilize KB as energy source
• Markedly reduces– glucose needs – protein catabolism for
gluconeogenesis
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Introduction of Clinical Case
10 m.o. girl – Overnight fast, morning seizures & coma– [glu] = 20mg/dl– iv glucose, improves rapidly
Family hx– Sister hospitalized with hypoglycemia at 8
and 15 mo., died at 18 mo after 15 hr fast
![Page 19: Fatty Acid Metabolism](https://reader035.fdocuments.net/reader035/viewer/2022070417/5681541a550346895dc21798/html5/thumbnails/19.jpg)
Introduction of Clinical Case
Lab values– RBC count, urea, bicarbonate, lactate, pyruvate, alanine,
ammonia all WNL– Urinalysis normal (no organic acids)
Monitored fast in hospital– @ 16 hr, [glu]=19mg/dl– No response to intramuscular glucagon– [KB] unchanged during fast– Liver biopsy, normal mitochondria, large accumulation of
extramitochondrial fat• [carnitine normal]• Carnitine acyltransferase activity undetectable
– Given oral MCT• [glu] = 140mg/dl (from 23mg/dl)• [Acetoacetate] = 86mg/dl (from 3mg/dl), similar for B-OH-
butyrate Discharged with recommendation of 8 meals per day
![Page 20: Fatty Acid Metabolism](https://reader035.fdocuments.net/reader035/viewer/2022070417/5681541a550346895dc21798/html5/thumbnails/20.jpg)
Resolution of Clinical Case Dx: hypoketonic hypoglycemia
– Hepatic carnitine acyl transferase deficiency CAT required for transport of FA into mito for
beta-oxidation Overnight fast in infants normally requires
gluconeogenesis to maintain [glu]– Requires energy from FA oxidation
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Resolution of Clinical Case
Lab values:– Normal gluconeogenic precursers (lac, pyr, ala)– Normal urea, ammonia– No KB
MCT do not require CAT for mitochondrial transport– Provides energy from B-oxidation for gluconeogenesis– Provides substrate for ketogenesis
Avoid hypoglycemia with frequent meals Two types of CAT deficiency (aka CPT deficiency)
– Type 1: deficiency of CPT-I (outer mitochondrial membrane)– Type 2: deficiency of CPT-2 (inner mitochondrial membrane)– Autosomal recessive defect
• First described in 1973, > 200 cases reported