Fatty acid metabolism
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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.

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Fatty Acid Metabolism

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Fatty acid metabolism

Fatty Acid Metabolism


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


Fatty acid metabolism

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


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