limited flux of glucose carbon past the
triose phosphate stage in glycolysis
(Forsberg et al., 1985), because of the high
demand for glycerol-3-phosphate for
triacylglycerol synthesis, and the active
metabolism of glucose in the pentose
phosphate pathway to produce NADPH.
The rate-limiting step in fatty acid
synthesis is catalysed by the enzyme
acetyl-CoA carboxylase (Hillgartner et al.,
1995). This enzyme converts acetyl-CoA to
malonyl-CoA, which is the actual ‘donor’
of acetyl units in the elongation process.
Two forms of the enzyme, termed and ,
are found in animals (Kim, 1997). The -
form is the enzyme found in lipogenic
tissues that regulates the rate of fatty acid
synthesis. The -form is found in non-
lipogenic tissues and is associated with
control of mitochondrial fatty acid oxida-
tion (discussed later). The -form of the
enzyme is subject to several levels of meta-
bolic regulation from signals of nutrient
status. Insulin, released when dietary
energy is plentiful, activates the enzyme
and so promotes fat storage. Increased
concentrations of citrate and isocitrate,
which also would signal increased sub-
strate availability for storage as fat, activate
the reaction. In contrast, glucagon and the
catecholamines inhibit its activity via
cyclic AMP (cAMP)-dependent phos-
phorylation. In this way, fat synthesis is
inhibited during times when mobilization
of energy stores is required. Increased con-
centrations of fatty acyl-CoA in the cytosol
inhibit the reaction, a form of negative
feedback. In addition to short-term changes
in enzyme activity caused by these
hormones and metabolites, the abundance
of the enzyme protein is also regulated.
Starvation decreases the amounts of both
the mRNA and the protein, while refeeding
after a fast causes a large increase in
transcription and translation of mRNA for
acetyl-CoA carboxylase (Hillgartner et al.,
1995).
The fatty acid synthase enzyme
complex consists of two multifunctional
polypeptide chains, each containing seven
distinct enzyme activities necessary to
elongate a growing fatty acid (Smith, 1994).
The two polypeptide chains are arranged
head-to-tail, resulting in two separate sites
for synthesis of fatty acids; thus each
enzyme complex can assemble two fatty
acids simultaneously. The activity of the
enzyme complex is not limiting to the
overall rate of fatty acid synthesis. The
overall reaction for synthesis of one
molecule of palmitic acid is:
Acetyl-CoA + 7 malonyl-CoA
+ 14 NADPH + 14 H+→palmitic acid
+ 7 CO 2 + 8 CoA + 14 NADP+
+ 6 H 2 O (5.1)In non-ruminants the hydrogen donor,
NADPH, is generated through metabolism
of glucose in the pentose phosphate path-
way and in the malic enzyme reaction. In
ruminants, cytosolic isocitrate dehydro-
genase can generate over one-half of the
NADPH needed through metabolism of
acetate (Beitz and Nizzi, 1997). The
remainder of the NADPH in ruminants is
derived from glucose metabolism in the
pentose phosphate pathway. The presence
of glucose enhances fatty acid synthesis in
ruminants, probably through enhanced
production of NADPH. Regulation of fatty
acid synthase is largely through intra-
cellular concentrations of dietary or synthe-
sized fatty acids, which decrease its activity
(Smith, 1994). High-fat diets decrease the
intracellular concentration of fatty acid
synthase, whereas refeeding after a fast
increases its concentration. High concen-
trations of insulin increase the abundance
of fatty acid synthase, whereas growth
hormone, glucagon and glucocorticoids
decrease its abundance (Hillgartner et al.,
1995).
Lipogenesis generally increases as
animals age, although changes are depot-
specific and may be modulated by diet
(Smith, 1995). Thus, lipogenesis in internal
adipose depots such as perirenal fat is
more active earlier in the growth stage, and
less active as the animal reaches physio-
logical maturity. Somatotropin treatment of
pigs and cattle leads to decreased lipo-
genesis, primarily by decreasing the sensi-
tivity of adipose cells to the actions of
insulin (Etherton and Bauman, 1998).Lipid Metabolism 105