fatty acid metabolism
Download
Skip this Video
Download Presentation
Fatty Acid Metabolism

Loading in 2 Seconds...

play fullscreen
1 / 21

Fatty Acid Metabolism - PowerPoint PPT Presentation


  • 70 Views
  • Uploaded on

Fatty Acid Metabolism. 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. Introduction of Clinical Case.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about ' Fatty Acid Metabolism' - evangeline-kline


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
introduction of clinical case
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
introduction of clinical case1
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
overview of fatty acid metabolism insulin effects figure 20 1
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
overview of fatty acid metabolism glucagon epinephrine effects figure 20 2
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
fatty acid synthesis figure 20 3
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
fatty acid synthesis pathway acetyl coa carboxylase
Fatty Acid Synthesis PathwayAcetyl 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
fatty acid synthesis pathway fa synthase complex figure 20 4
Fatty Acid Synthesis PathwayFA Synthase Complexfigure 20-4
  • Priming reactions
    • transacetylases
  • (1) condensation rxn
  • (2) reduction rxn
  • (3) dehydration rxn
  • (4) reduction rxn
regulation of fa synthesis acetyl coa carboxylase
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
regulation of fa synthesis acetyl coa carboxylase figure 20 5
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
lipid metabolism in fat cells fed state figure 20 6
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
lipid metabolism in fat cells starved or exercising state figure 20 6
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
oxidation of fatty acids the carnitine shuttle figure 20 7
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
b oxidation figure 20 8
B-Oxidationfigure 20-8
  • FAD-dependent dehydrogenation
  • hydration
  • NAD-dependent dehydrogenation
  • cleavage
slide15
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
hepatic ketone body synthesis figure 20 11
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
utilization of ketone bodies by extrahepatic tissues figure 20 11
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
introduction of clinical case2
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
introduction of clinical case3
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
resolution of clinical case
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
resolution of clinical case1
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
ad