section 22.6

Lipid Homeostasis

507

Epinephrine

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

succinate.

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