Transcript Fatty Acid Oxidation - New Jersey Medical School

Fatty Acid Oxidation Defects
1. 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.
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.
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
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 -> Insulin inhibits lipolysis
Free fatty acids are bound by serum albumin -> serves
as carrier in blood
FA in
Plasma
FA
Bound to FABP
FAO Cycle
Steps in the oxidation of Palmitoleic Acid
(C:16:1)
1) CH3-CH2-CH2-CH2-CH2-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2CO-SCOA +CH3-CO-CoA + FADH2 +NADH
2) CH3-CH2-CH2-CH2-CH2-CH2-CH=CH-CH2-CH2-CH2-CO-SCoA
+ CH3-CO-CoA + FADH2 +NADH
3) CH3-CH2-CH2-CH2-CH2-CH2-CH=CH-CH2-CO-SCoA+
CH3-CO-CoA + FADH2 +NADH
4) CH3-CH2-CH2-CH2-CH2-CH=CH-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-COCoA) + 6FADH2 + 7NADH
8
Oxidation of Odd Chain FA
Omega Oxidation of Fatty Acids
11
Fattyacyl
CoA
Regulation of FAO
1.
2.
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
Triacyl glycerol or Hormone
sensitive lipase
•
•
•
Glucagon
Epinephrine
Insulin
Spectrum of FAO deficiencies
1.
Carnitine deficiency
2.
Fattyacyl CoA synthetase deficiency
3.
Short chain (SCAD), medium chain (MCAD), long chain (LCAD)
and multi-chain (MCAD) dehydrogenase mutations
4.
Acyl Carnitine-Carnitine translocase mutations
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 1:8456 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.
A Child has MCAD deficiency
Will this child be:
A. Hypoglycemic
B. Hyperglycemic
C. Normal glucose
Will this child be:
A. Severely ketotic
B. Mildly ketotic
C. Not ketotic
Will this child have:
A. Acidosis
B. Alkalosis
C. Normal pH.
Learning Objectives
This lecture links defects in catabolism of lipids to a variety of
pathological states. Following this lecture students should
understand that
1.
2.
3.
4.
5.
6.
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