Nutrition and Metabolism of Lipids 119How do dietary fatty acids infl uence serum
cholesterol and triacylglycerols?
In common with other physiological systems, lipo-
protein metabolism is coordinated by interplay
between the activity of specifi c genes and hormones
that determines the production and activity of func-
tional proteins (enzymes, receptors, lipid transfer, and
apoproteins). Effects on these functional proteins
ultimately regulate the quantity and quality of circu-
lating lipids and lipoproteins. While there have been
signifi cant advances in knowledge of the modulatory
effects of dietary fatty acids on hormones and gene
expression, evidence for the effects of dietary fats on
functional proteins is by far the most advanced.
Saturated fatty acids and low-density
lipoprotein cholesterol
The most well-elucidated mechanism to explain how
different dietary fats produce variable effects on LDL-
cholesterol is through the LDL receptor pathway, the
control of which has already been described (see
Section 6.5). The ability of the cell to regulate its pool
of free cholesterol depends to a large extent on the
nature of the fatty acids available for esterifi cation by
the enzyme ACAT, an intracellular relative of LCAT.
ACAT favors unsaturated fatty acids (MUFAs and
PUFAs) as substrates for esterifi cation, which utilizes
free cholesterol within the cell. The resulting reduc-
tion in intracellular free cholesterol stimulates the
transcription of the LDL receptor gene and produc-
tion of new LDL receptors through the SREBP mech-
anism, and fall in circulating LDL as already described.
Conversely, SFAs are poor substrates for ACAT, and
their presence in the cell exerts the opposite effect on
free cholesterol levels, thus increasing circulating LDL
cholesterol and total serum cholesterol (Figure 6.8).
Fatty acids may also exert direct effects on the activity
of LDL receptors by altering the composition of
membrane phospholipids and thus membrane fl uid-
ity. Alternatively, there is evidence to suggest that
dietary PUFA could upregulate LDL receptors indi-
rectly, by increasing the cholesterol content (litho-
genicity) of bile and in this way accelerate the excre-
tion of cholesterol.
Long-chain n-3 polyunsaturated fatty acids
and serum triacylglycerols
Long chain n-3 PUFAs have potent effects in the liver,
where they suppress the production of endogenous
TAG by inhibiting the enzymes phosphatidic acid
phosphatase and diacylglycerol acyltransferase. They
may also selectively increase the degradation of apoB-
100, further reducing the production of TAG-rich
VLDLs. (Note that apoB-100 is produced constitu-
tively, so that the production of VLDL is driven by the
supply of substrates for the synthesis of TAG). In
addition, long-chain n-3 PUFAs accelerate the clear-
ance of TAG-rich lipoproteins from the circulation in
the postprandial phase by stimulating the activity of
LPL. Together, these effects are thought to underlie
the ability of these fatty acids to correct the lipopro-
tein abnormalities associated with an ALP. It is also
possible that many of the effects of eicosapentaenoic
acid/docosahexaenoic acid on blood lipids and other
cardiovascular risk factors are mediated through an
increase in the sensitivity of tissues to the action of
insulin. However, there is, as yet, no convincing evi-
dence to support such an effect in adipose tissue, liver,
or skeletal muscle.Nutrient–gene interactions
It has been estimated that diet could account for up
to 50% of the variation in blood lipids and lipopro-
tein levels between individuals. This would mean that
genetic differences must explain the remaining 50%.
In real terms, interactions between diet and genes
represent a sizeable proportion of each of these unre-
alistically discrete fractions.Fixed genetic polymorphisms
Variation in the structure of specifi c genes between
individuals (genetic heterogeneity) has been shown to
give rise to differences in dietary responsiveness. A
few common polymorphisms have been identifi ed in
genes associated with lipoprotein metabolism, the
best example of which is apoE. ApoE facilitates the
uptake of TAG-rich lipoproteins (chylomicron rem-
nants and VLDL) via the remnant and LDL receptors
and, thus, in part, determines the removal of TAG
from the circulation. The gene for apoE is polymor-
phic, which means that it exists in multiple forms
between individuals. This polymorphism generates
several isoforms of the protein that express variable
affi nities for their receptors and thus variable poten-
tial to remove TAG-rich lipoproteins from the circu-
lation. In this way, apoE genotype can modulate the
response of an individual to any dietary fat that exerts
an infl uence on TAG-rich lipoproteins, giving rise to