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Section XI - Fatty Acid Metabolism
I. Fatty acid synthesis
A. Occurs primarily in the liver and mammary
glands (primarily stored in adipocytes).
B. During high energy states ATP and NADH inhibit
isocitrate dehydrogenase → ↑ citrate
C. ↑ citrate → upregulation of acetyl-CoA
carboxylase (requires biotin) → ↑ fatty acid
synthesis
D. Malonyl-CoA is synthesized during fatty acid
synthesis and inhibits fatty acid catabolism via
inhibition of carnitine acyltransferase I (CAT I).
E. NADPH (produced from the HMP shunt) is
necessary for the synthesis of fatty acids.
Figure 2.5.13 - Fatty acid
II. Fatty acid catabolism
A. Occurs in muscle, liver, and other tissues
with a mitochondrial matrix but does
not occur in the brain (brain must rely
on glucose and ketones) or RBCs (lack
mitochondria).
B. Triglycerides are stored in adipocytes and
metabolized to fatty acids and glycerol via
hormone sensitive lipase (HSL).
1. HSL is activated by stress (glucagon,
catecholamines, and ACTH) and
inhibited by insulin.
C. Glycerol is transported to the liver to be
used for gluconeogenesis.
D. Fatty acids are transported throughout the
body to be used for energy in most tissues
(not brain or RBCs).
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E. The mitochondrial matrix is impermeable to

long-chain fatty acids (LCFA). LCFAs can only
enter the mitochondrial matrix through the
carnitine shuttle.

III. Systemic primary carnitine deficiency

A. A defect in the transporter protein that allows
carnitine to be shuttled into the mitochondrial
matrix.
B. The kidneys normally reabsorb carnitine and
a similar defective protein in the kidneys → ↓
carnitine and acyl-carnitine
C. ↓ beta oxidation → ↓ ketones
D. ↓ acetyl-CoA → ↓ pyruvate carboxylase
activity → ↓ gluconeogenesis → hypoglycemia

E. ↑ LCFA → liver damage → ↑ ammonia →

encephalopathy
F. Treatment includes carnitine supplementation

IV. Medium-chain acyl-CoA dehydrogenase (MCAD)

deficiency
A. A defective medium-chain acyl-CoA
dehydrogenase
B. Similar to primary systemic carnitine deficiency
(hypoketotic hypoglycemia, liver dysfunction,
and encephalopathy)
C. Carnitine and acyl-carnitine levels are normal
D. LCFAs levels are normal (unless LCAD deficiency)

REVIEW QUESTIONS
1. A 26-year-old female presents with a 2-month
history of constipation, depression, and kidney
stones. She has also noticed white discharge
from both nipples during this time and thinks
she may be lactating even though she has no
children. Over the past several days she has
experienced several episodes of syncope. She
states that several of her family members have
been diagnosed with “calcium problems.” An
initial blood glucose measurement reveals
hypoglycemia. How will the activity of carnitine
acyltransferase I (CAT I) likely be altered in this
patient?
• MEN1 (pituitary, pancreatic, and parathy-
roid tumors)
• Parathyroid adenoma → hypercalcemia →
constipation, depression, and kidney stones
• Prolactinoma → white discharge from both
nipples
• Insulinoma → several episodes of syncope
due to hypoglycemia
• Insulin increases the activity of acetyl-CoA
carboxylase → ↑ malonyl-CoA → inhibition
of carnitine acyltransferase I
119
?
2. A previously healthy 10-year-old Jewish boy is
brought to the ED by his mother who states that
he developed nausea and vomiting followed
by a syncopal episode after participating in
a fast for Yom Kippur. Labs are significant for
hypoglycemia and non-detectable levels of
acetoacetate. A muscle biopsy reveals normal
levels of a protein responsible for transporting
long-chain fatty acids into the mitochondrial
matrix. It is determined that impairment of
gluconeogenesis likely resulted in hypoglycemia.
Decreased activity of what enzyme involved
in gluconeogenesis most likely explains these
findings?
• Hypoketotic hypoglycemia during a fast →
MCAD deficiency or systemic primary carni-
tine deficiency
• “A muscle biopsy reveals normal levels of a
protein responsible for transporting long-
chain fatty acids into the mitochondrial
matrix” is describing carnitine → patient
does not have systemic primary carnitine
deficiency
• MCAD deficiency → ↓ acetyl-CoA → ↓
pyruvate carboxylase → hypoglycemia