mitochondrial matrix. Consequently,
oxidation of these fatty acids is not con-
trolled by CPT-I.
The activity of CPT-I is inhibited by
interaction with malonyl-CoA, the product
of the first committed step of lipogenesis
catalysed by acetyl-CoA carboxylase.
Insulin stimulates the activity of acetyl-
CoA carboxylase. Conditions of negative
energy balance as signalled by lower ratios
of insulin to glucagon thus result in
decreased concentrations of malonyl-CoA
and increased rates of fatty acid oxidation.
Furthermore, in rats, the sensitivity of CPT-I
to malonyl-CoA is decreased during times
of low insulin or insulin resistance, which
decreases the ability of the low concentra-
tions of malonyl-CoA to inhibit acyl-
carnitine formation and thereby further
increases the rate of fatty acid oxidation
(Zammit, 1996).
Classical studies (reviewed by McGarry
et al., 1989) that delineated the control of
CPT-I by malonyl-CoA in rats described this
mechanism as a means of preventing simul-
taneous oxidation and synthesis of fatty
acids within the liver cell, a potential futile
cycle. However, in cattle, sheep and swine,
rates of lipogenesis are very low in liver,
which obviates the need for such a control
mechanism. Nevertheless, production of
malonyl-CoA by acetyl-CoA carboxylase
does occur in bovine, ovine and swine liver
(Brindle et al., 1985), probably as a control
mechanism for oxidation rather than as a
quantitatively important site of fatty acid
synthesis. Likewise, skeletal muscle and
heart muscle are also non-lipogenic tissues
that use fatty acids as energy sources. Both
heart and skeletal muscle of rats contain a
high activity of acetyl-CoA carboxylase of
the -isoform (Kim, 1997). Physiological
situations that lead to low insulin to
glucagon ratios and decreased activity of
acetyl-CoA carboxylase in these tissues
result in increased rates of fatty acid oxida-
tion. Whether the acetyl-CoA carboxylase
present in the liver of ruminants and swine
is similar to the -isoform of rats has not
been determined.
Intramitochondrial oxidation of fatty
acyl-CoA occurs through the -oxidation
pathway, resulting in formation of acetyl-
CoA. During this process, electrons are
transferred to FAD and NAD+to form the
reduced forms of these coenzymes, which
in turn can donate electrons to the electron
transport chain to drive ATP synthesis. The
acetyl-CoA can be oxidized completely to
carbon dioxide in the tricarboxylic acid
(TCA) cycle. Alternately, acetyl-CoA can be
diverted to formation of ketone bodies.
Ketogenesis is enhanced in times of
increased fatty acid mobilization and
uptake by the liver, when low ratios of
insulin to glucagon cause activation of
CPT-I that allows extensive uptake of fatty
acids into mitochondria (Zammit, 1990).
Conversion of acetyl-CoA to ketone bodies
rather than complete oxidation in the TCA
cycle results in formation of less ATP per
mole of fatty acid oxidized. For example,
complete oxidation of palmitate in the TCA
cycle, followed by oxidative phosphoryla-
tion in the electron transport chain, yields
129 ATP per molecule of palmitate. In
contrast, -oxidation of palmitate with
acetyl-CoA converted to ketone bodies
generates only 27 ATP per molecule of
palmitate. Because the production of ATP
must match its utilization for energy-
requiring reactions in the liver, ketogenesis
allows the liver to metabolize about five
times more fatty acid for the same ATP
yield. Conversion of fatty acids into water-
soluble fuels may be an important strategy
to allow the animal to cope with extensive
mobilization of fatty acids during energy
deficit.
In addition to control at the levels of
fatty acid supply and CPT-I, ketogenesis is
controlled by the activity of the key regula-
tory enzyme, 3-hydroxy-3-methylglutaryl-
CoA (HMG-CoA) synthase. This enzyme is
controlled both through increased tran-
scription and translation during prolonged
energy deficit and by inactivation through
succinylation (Emery et al., 1992).
Increased flux of metabolites such as
pyruvate, propionic acid or glucogenic
amino acids into the TCA cycle, resulting
from greater feed intake and improved
energy balance, results in increased pool
size of succinyl-CoA, an intermediate of110 J.K. Drackley