section 22.6
Lipid Homeostasis
F I G U R E 2 2 - 2 2
Ketone body production and utilization. Ketone bodies are produced in the liver from fatty acids derived from adipocyte
lipolysis. They are released and used as fuel in peripheral tissues. The initial step in acetoacetate metabolism is activation
to acetoacetyl-CoA by succinyl-CoA. HMG-CoA, /S-hydroxy-/j-methylglutaryl-CoA; HB, /i-hydroxybutyrate.
across the inner mitochondrial membrane. The transport
is a transesterification process and involves carnitine and
two enzymes, carnitine palmitoyltransferase (CPT) types
I and IL CPTI is inhibited by malonyl-CoA, primary sub-
strate for fatty acid synthesis that occurs in the cytosol. In
the presence of a low insulin:glucagon ratio, malonyl-CoA
formation is inhibited, leading to active CPTI and promot-
ing fatty acid oxidation and consequent ketone body pro-
duction. The opposite situation occurs at a high insulin:
glucagon ratio.
Hepatic /1-oxidation, without oxidation of acetyl-CoA
through the TCA cycle, produces a substantial amount
of energy. At such a time, liver is actively engaged in
gluconeogenesis so that mitochondrial oxaloacetate is de-
pleted, TCA cycle activity is depressed, and acetyl-CoA
levels rise. The last reaction in /3-oxidation is conversion of
acetoacetyl-CoA to acetyl-CoA, with an equilibrium in fa-
vor of high levels of acetoacetyl-CoA. Thus, acetyl-CoA
and acetoacetyl-CoA accumulate and form HMG-CoA;
cleavage of this last compound yields acetoacetate, which
is reduced to /3 - h y d ro x y bu ty ra t e. Acetone results from
nonenzymatic decarboxylation of acetoacetate. Ketone
body formation occurs exclusively in liver (see Chapter 18)
and is prominent in starvation and diabetes owing to the
low insulimglucagon ratio in these conditions. The ketone
bodies readily leave the liver and enter the bloodstream.
Acetone is eliminated in the urine and exhaled by the lungs.
Because of its odor, it has long been diagnostic in urine
and in breath in clinical situations. Because production
of ketone bodies was associated with starvation and dis-
ease, these compounds were not considered to be metaboli-
cally useful. During periods of starvation, acetoacetate and
/3 -hyd roxybutyrate make a considerable contribution to
fuel homeostasis. The ratio of their plasma concentra-
tions in starvation and diabetes is about 1:5, reflecting
high hepatic levels of NADH, which favors the reduc-
tion of acetoacetate to /i-hydroxybutyrate. In utilization
of ketone bodies in skeletal muscle, /i-hydroxybutyrate
is converted to acetoacetate and then to acetoacetyl-CoA,
which is cleaved, and the acetyl-CoA formed is oxidized
through the TCA cycle. Activation of acetoacetate to
acetoacetyl-CoA requires conversion of succinyl-CoA to
Under normal conditions, the brain cannot use ketone
bodies because it lacks the enzyme needed to activate ace-
toacetate. However, this enzyme is induced in brain after
about 4 days of starvation, permitting the brain to obtain
40-70% of its energy from ketone body oxidation while
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