370
chapter 18
Lipids
i:
Fatty Acids and Eicosanoids
Fatty acids
Activation to CoA derivatives
Carnitine mediated translocation
into mitochondria
Fatty acids CoA
Mitochondrial electron transfer
flavoprotein (ETF) and
■
ETF-Ubiquinone oxidoreductase
NADH -
Turns in
[5-oxidation Spiral
Main mitochondrial respiratory chain
In Liver
Acetoacetate,
Acetyl CoA
-------------►
(L-hydroxybutyrate
(Ketone bodies)
FADH, NADH
Energy utilized in:
1. liver for conversion
of ammonia into
urea and gluconeogenesis
2. cardiac and
muscle contraction
Oxidation in
extrahepatic
tissues
(including brain)
Pyruvate
Gluconeogenesis in liver
Glucose (Maintenance of
optimal metabolism, in
particular in the brain
during fasting)
FIGURK 18-4
Spectrum of consequences of defects in fatty acid oxidation. The primary effect is inadequate production of acetyl-CoA,
which leads to decreased flux through the TCA cycle and lack of ketone body synthesis in the liver. Both of these events
cause energy deficits and changes in metabolic regulatory processes. Alterations in hepatic metabolism lead to
hypoglycemia and hyperammonemia. Abnormalities also occur in skeletal and cardiac muscle and in the central nervous
system.
The MCAD deficiency primarily affects hepatic
fatty acid oxidation and the most common clinical
presentation is episodic hypoketotic hypoglycemia
initiated by fasting. The major metabolic derangement
in MCAD is an inadequate supply of acetyl-CoA
(Figure 18-4). The deficiency of acetyl-CoA leads to a
decreased flux through the tricarboxylic acid (TCA)
cycle causing diminished ATP production, decreased
ketone body formation (the ketone bodies are
metabolites used by the extrahepatic tissues),
decreased citrate synthesis, and decreased
oxaloacetate synthesis from pyruvate catalyzed by
pyruvate carboxylase for which acetyl-CoA is the
primary activator. The decreased flux through the
TCA cycle during deficiency of acetyl-CoA causes a
diminished synthesis of citrate from oxaloacetate and
acetyl-CoA, as well as inhibition of a-ketoglutarate
dehydrogenase due to an elevated ratio of fatty
acyl-CoA to CoA. The formation of oxaloacetate is
crucial for gluconeogenesis (Chapter 15).
Accumulation of octanoate, which occurs in MCAD,
may be responsible for encephalopathy and cerebral
edema. In
Reye’s syndrome,
octanoate also is elevated
and may be responsible for its phenotypical similarity
with MCAD. MCAD is managed with avoidance of
fasting, stress, and treatment with intravenous glucose
during acute episodes.
2. Enoyl-CoA hydratase catalyses the hydration of A2
unsaturated acyl-CoA. This enzyme has broad
specificity and can act on
a-, ft-
(or A2-) unsaturated
CoA in trans or cis configuration. The products
formed are
2-fram-Enoyl-CoA -> L(+)-/3-hydroxyacyl-CoA
[or L(+)-3-hydroxyacyl-CoA]
2-c/x-Enoyl-CoA
—>
D(—
)-/l-hydroxyacyl-CoA
[or
D(—
)-3-hydroxyacyl-CoA]
