section 18.2
Metabolism of Ketone Bodies
375
9
10
O leyl-C oA
3 Acetyl-CoA • > | p-iO xidations
4
SC oA
A
3
-c/s-Enoyl-CoA
(inactive substrate inß-oxidation)
|A
3
-c/s-A
2
-frans-
\
Enoyl-CoA isom erase
O
.c—
A f/ans-E n oyl-C oA
(normal substrate in ß -oxidation)
I
ß-O xidation
SC oA
6
Acetyl-CoA
F IG U R E 1 8 -7
Oxidation of oleic acid.
synthesized in liver mitochondria. The overall steps in-
volved in the formation of ketone bodies include the mo-
bilization of fatty acids by lipolysis from adipose tissue
triacylglycerol by hormone-sensitive triacylglycerol li-
pase, plasma fatty acid transport, fatty acid activation,
fatty acid transport into mitochondria (with acylcami-
tine as an intermediate), and /1-oxidation. The regula-
tory reactions are those of lipolysis and of acyl-CoA
transport across the mitochondrial membrane (CPTI).
Synthesis of ketone bodies from acetyl-CoA consists
of three steps: formation of acetoacetyl-CoA, forma-
tion of acetoacetate, and reduction of acetoacetate to
ß-
hydroxybutyrate. Nonenzymatic decarboxylation of ace-
toacetate yields acetone, which is eliminated via the
lungs.
The pathways of formation of ketone bodies are shown
in Figure 18-9. The major pathway of production of
acetoacetate is from /l-hydroxy-/l-methylglutaryl-CoA
(HMG-CoA). Hydrolysis of acetoacetyl-CoA to acetoac-
etate by acetoacetyl-CoA hydrolase is of minor impor-
tance because the enzyme has a high
Km
for acetoacetyl-
CoA. HMG-CoA is also produced in the cytosol, where
it is essential for the synthesis of several isoprenoid com-
pounds and cholesterol (Chapter 19). The reduction of
acetoacetyl-CoA to /i-hydroxybutyrate depends on the
mitochondrial [NAD+]/[NADH] ratio.
Ketone bodies are oxidized primarily in extrahepatic tis-
sues (e.g., skeletal muscle, heart, kidney, intestines, brain)
within mitochondria,
ß
-Hydroxybutyrate
is
oxidized
to acetoacetate by NAD+-dependent /1-hydroxybutyrate
dehydrogenase by reversal of the reaction that occurred
during ketogenesis:
CH3CH(OH)CH2CCr + NAD+ ->
D-/3-Hydroxy butyrate
CH3COCH2COO- + NADH + H+
acetoacetate
Activation of acetoacetate requires transfer of coen-
zyme A from succinyl-CoA, derived from the TCA
cycle,
by
succinyl-CoA-acetoacetate-CoA
transferase
(thiophorase):
C H
2
C O S C oA
C H jC O C T
C H jC O C T C H
2
C O S C oA
I
+
I
*■
I
+ 1
C H 2C O C r
C O C H
3
C H 2C O C T C O C H
3
S u ccin y l-
A c e to -
S u c c in a te A c e to a c e ty l-
C oA
a c e ta te
C oA
The activation occurs at the expense of conversion of
succinyl-CoA to succinate in the TCA cycle and formation
of GTP (Chapter 13). Acetoacetyl-CoA is cleaved to two
molecules of acetyl-CoA by acetyl-CoA acetyltransferase,
the same enzyme involved in the synthesis of acetoacetyl-
CoA (Figure 18-9). Acetyl-CoA is oxidized in the TCA
cycle. Thus, formation of ketone bodies in the liver and
their oxidation in extrahepatic tissues are dictated by the
ratio [substrates]/[products].
