Fatty Acid Oxidation Defects

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Fatty Acid Oxidation Defects

• The disorders of oxidation of fatty acids by
  mitochondria has been major focus of research
  for the past 10-20 years. Based on these studies
  clinicians are now beginning to understand
  symptoms of Reyes-like syndrome, cardiomyopathy,
  hypotonia, hypoglycemia, developmental delay, and
  in some cases sudden infant death syndrome
  (SIDS). These are all related to defects in FAO.
• 2. Panel of assays in neonates now include
  quantization of FAO enzymes specifically MCAD.

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Fatty Acids are preferentially oxidized

1. During periods of extended exercise e.g.
   aerobics, running on a treadmill, running for
   long distances.
2. In diabetic patients in whom glucose metabolism
   is low.
3. During periods of starvation.
4. By heart muscle which almost exclusively depends
   on FA oxidation for energy.

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Sequential Steps in the oxidation of Fatty Acids

• Mobilization of Fat from adipose tissue
• Transport of fatty acids in plasma and their
  activation in the cells
• Transport of activated fatty acids to
  mitochondria and oxidation
• Formation of ketone bodies (excess oxidation in
  starvation and diabetes)
• Regulation of fatty acid oxidation

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Mobilization of Triacylglycerols That are Stored
in Adipocyte Cells
Free fatty acids and glycerol are released into
the blood stream
Lipolysis inducing hormones Epinephrine,
glucagon, adrenocorticotropic hormones -gt
Insulin inhibits lipolysis Free fatty acids are
bound by serum albumin -gt serves as carrier in
blood
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FA Bound to FABP
FA in Plasma
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FAO Cycle
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Steps in the oxidation of Palmitoleic Acid
(C161)

• CH3-CH2-CH2-CH2-CH2-CH2-CHCH-CH2-CH2-CH2-CH2-CH2-
  CO-SCOA CH3-CO-CoA FADH2 NADH
• CH3-CH2-CH2-CH2-CH2-CH2-CHCH-CH2-CH2-CH2-CO-SCoA
  CH3-CO-CoA FADH2 NADH
• CH3-CH2-CH2-CH2-CH2-CH2-CHCH-CH2-CO-SCoA
• CH3-CO-CoA FADH2 NADH
• CH3-CH2-CH2-CH2-CH2-CHCH-CO-SCoA CH3-CO-CoA
  FADH2 NADH
• 5) CH3-CH2-CH2-CH2-CH2-CO-SCoAA CH3-CO-CoA
  NADH
• 6) CH3-CH2-CH2-COA CH3-CO-CoA FADH2 NADH
• 7) CH3-CO-CoA CH3-CO-CoA FADH2 NADH After
  the 7th round you are left with an 8th acetyl CoA
  (CH3-CO-CoA) 6FADH2 7NADH

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Oxidation of Odd Chain FA
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Omega Oxidation of Fatty Acids
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Fattyacyl CoA
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Regulation of FAO

• 1. Enzyme CPTI (carnitine-palmitoyl transferase
  I) is the rate limiting enzyme. It is inhibited
  by Malonyl CoA, a product formed during fatty
  acid synthesis
• Hormonal Regulation of FA oxidation
• Glucagon
• Epinephrine
• Insulin

Triacyl glycerol or Hormone sensitive lipase
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• Spectrum of FAO deficiencies
• Carnitine deficiency
• Fattyacyl CoA synthetase deficiency
• Short chain (SCAD), medium chain (MCAD), long
  chain (LCAD) and multi-chain (MCAD) dehydrogenase
  mutations
• Acyl Carnitine-Carnitine translocase mutations

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Examples of Clinical Findings
The clinical entity known as MCAD deficiency was
biochemically defined about 20 years ago
however, some believe the condition to be at
least as common in newborns as phenylketonuria,
with an incidence approximating 1 per every
12,000 live births. A recent report from Europe
indicates an incidence in Bavaria of 18456 in
more than 500,000 newborns screened
Another report from England Of 62 affected
individuals identified, 57 were from England,
giving an incidence of 4.5 cases/100?000 births.
Forty six cases presented with an acute illness
(10 of whom died), 13 cases were identified
because of family history, and three for other
reasons. Six of the survivors were neurologically
impaired. Undiagnosed, MCAD deficiency results
in considerable mortality and morbidity. However,
current management improves outcome.
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A Child has MCAD deficiency

• Will this child be
• Hypoglycemic
• Hyperglycemic
• Normal glucose
• Will this child be
• Severely ketotic
• Mildly ketotic
• Not ketotic
• Will this child have
• Acidosis
• Alkalosis
• Normal pH.

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Learning Objectives

• This lecture links defects in catabolism of
  lipids to a variety of pathological states.
  Following this lecture students should understand
  that
• oxidation of lipids is an important energy source
• oxidation requires mobilization of fat from
  adipose cells in response to hormones like
  glucagon and epinephrine by a mechanism in which
  cellular cAMP is increased
• fatty acids transported in plasma have to be
  activated
• activated fatty acids need to be transported from
  cytosol to mitochondrial matrix where oxidation
  takes place and this regulation has important
  implications for energy production and pathology
• in diabetics excess fatty acids oxidized produce
  ketone bodies as metabolites which are important
  source of energy for muscle , heart and brain
• the presence of ketone bodies in plasma leads to
  acidosis which affects oxygen saturation of Hb
  and resultant delivery of oxygen to tissues