Nutrition and Metabolism of Lipids 107The effi ciency of fatty acid oxidation depends on
the availability of oxaloacetate and, hence, concurrent
carbohydrate oxidation. β-Oxidation of saturated
fatty acids appears to be simpler than oxidation of
unsaturated fatty acids because, before the acetyl-
CoA cleavage, it involves the formation of a trans
double bond two carbons from the CoA. In contrast,
β-oxidation of unsaturated fatty acids yields a double
bond in a different position that then requires further
isomerization or hydrogenation. From a biochemical
perspective, this extra step appears to make the oxida-
tion of unsaturated fatty acids less effi cient than that
of saturated fatty acids. However, abundant in vivo
and in vitro research in both humans and animals
clearly shows that long-chain cis-unsaturated fatty
acids with one to three double bonds (oleate, linole-
ate, α-linolenate) are more readily β-oxidized than
saturated fatty acids of equivalent chain length, such
as palmitate and stearate. The oxidation of PUFA
and monounsaturates in preference to saturates has
potential implications for chronic diseases such as
coronary artery disease because their slower oxida-
tion implies slower clearance from the blood, thereby
providing more opportunity for esterifi cation to cho-
lesterol and subsequent deposition in the vessel wall.
In peroxisomes, fatty acid β-oxidation is a trun-
cated process by which long-chain PUFAs are chain
shortened. This peroxisomal detour has been identi-
fi ed as an obligatory step in the endogenous synthesis
of docosahexaenoate from eicosapentaenoate.
Odd-carbon long-chain fatty acids are relatively
uncommon but, when β-oxidized, yield propionyl-
CoA, the further β-oxidation of which requires biotin
and vitamin B 12 as coenzymes.
Ketogenesis and ketosis
Large amounts of free fatty acids inhibit glycolysis
and the enzymes of the tricarboxylic acid cycle,
thereby impairing production of oxaloacetate. When
insuffi cient oxaloacetate is available to support the
continued oxidation of acetyl-CoA, two acetyl-CoA
molecules condense to form a ketone, acetoacetate.
Acetoacetate can be spontaneously decarboxylated to
form acetone, a volatile ketone, or converted to a third
ketone, β-hydroxybutyrate. When glucose is limiting,
ketones are an alternative source of energy for certain
organs, particularly the brain. They are also effi cient
substrates for lipid synthesis during early postnatal
development. Conditions favoring ketogenesis include
starvation, diabetes, and a very high-fat, low-
carbohydrate “ketogenic” diet.Carbon recycling
Carbon recycling is the process by which acetyl-CoA
derived from β-oxidation of one fatty acid is incor-
porated into another lipid instead of completing the
β-oxidation process to carbon dioxide. In principle,
all fatty acids undergo this process to some extent but
it is most clearly evident for two PUFAs, linoleate and
α-linolenate. Carbon recycling captures the over-
whelming majority of α-linolenate carbon, i.e., about
10 times more than is incorporated into docosahexae-
noate, which remains in the body of suckling rats 48
hours after dosing with uniformly^13 C-labeled α-lino-
lenate. Carbon recycling of linoleate in the rat cap-
tures similar amounts of the linoleate skeleton to
those of arachidonate, the main desaturation and
chain-elongation product of linoleate. Hence, carbon
recycling appears to be a ubiquitous feature of the
metabolism of PUFA, although its biological signifi -
cance is still unclear.Peroxidation
Peroxidation (auto-oxidation) is the nonenzyme-cat-
alyzed reaction of molecular oxygen with organic
compounds to form peroxides and related breakdown
products. PUFAs are particularly vulnerable to peroxi-
dation at the double bonds. Initiating agents such as
pre-existing peroxides, transition metals, or ultraviolet
or ionizing radiation produce singlet oxygen. Singlet
oxygen can then abstract hydrogen at the double bonds
of polyunsaturates to produce free (peroxy) radicals,
which abstract further hydrogens from the same or
different fatty acids and propagate the peroxidation
process. Eventually, this leads to termination by the
formation of stable degradation products or hydro-
peroxides (Figure 6.12). Trans isomers are frequently
formed during the process. Hydroperoxides can form
further hydroperoxy radicals or can be reduced by
antioxidants, which contain thiol groups, i.e., glutathi-
one and cysteine. Peroxidation of dietary fats gives rise
to aldehydes, i.e., 2-undecenal, 2-decenal, nonanal, or
octanal, which have a particular odor commonly
known as rancidity.
Since peroxidation is a feature of polyunsaturates,
it is a potential hazard facing most membranes and
dietary lipids. Antioxidants such as vitamin E are
usually present in suffi cient amounts to prevent or