Introduction to Human Nutrition

Nutrition and Metabolism of Lipids 115

amounts of cholesterol from the circulation, i.e., from
the diet or from synthesis outside the brain. This has
been extensively studied in the young rat and sup-
porting, although inconclusive, evidence is also avail-
able for the pig. The brain has suffi cient capacity to
synthesize cholesterol from acetyl-CoA derived pri-
marily from either glucose or ketones. Hence, it
achieves the required level of cholesterol apparently
entirely by endogenous synthesis. In neonates, ketones
appear to play a greater role as substrates for brain
cholesterol than in adults, in whom their main func-
tion seems to be as an alternative fuel to glucose.
Among the common dietary long-chain fatty acids
that would give rise to ketones during fat oxidation,
PUFAs, particularly linoleate and α-linolenate, appear
to be the best substrates for ketogenesis, since carbon
from these fatty acids readily appears in brain choles-
terol in suckling rats.

6.11 Effect of diet on serum lipids
and lipoproteins

Diet and serum cholesterol

Diet exerts a profound infl uence on blood lipids and
lipoproteins and, as such, should always be a major
component of strategies for the primary prevention
of diseases in which lipids play an etiological role,
such as CHD. Nevertheless, despite convincing epide-
miological evidence and the existence of credible
biochemical mechanisms to support a relationship
between dietary fat and serum cholesterol, the
outcome of prospective intervention trials designed
to test this relationship within populations has been
disappointing.

Over 30 years ago Keys and Hegsted made the land-

mark observation that variation in the concentration

of serum cholesterol across seven different countries

was positively related to the amount of energy derived

from saturated fat. Conversely, they found that intake

of dietary PUFA was inversely related to serum cho-

lesterol. From this fi nding they were able to formulate

equations that enabled them to predict the quantita-

tive effect of saturated and polyunsaturated fat on

serum cholesterol (Figure 6.16). In simpler terms, the

ratio of PUFAs to saturated fatty acids (SFAs), the

P : S ratio, was used with effect to predict changes in

serum cholesterol. Although still effective today, the

equations and P:S ratio are being superseded by

advanced knowledge of the biological effects of indi-

vidual fatty acids. It is now well established that satu-

rated fats with between 12 and 16 carbon atoms,

namely lauric, myristic, and palmitic acids, are par-

ticularly hypercholesterolemic, whereas stearic acid,

an extremely abundant SFA in most diets, is relatively

neutral in its effects on serum cholesterol. [Note that

stearic acid is desaturated to monounsaturated fatty

acids (MUFAs) by Δ^9 desaturase]. The cholesterol-

raising effect of SFAs arises chiefl y from an increase

in LDL cholesterol and is about twice as potent as the

hypocholesterolemic effect of dietary PUFAs. Para-

doxically, SFAs actually increase serum HDL choles-

terol. The polyunsaturates are divisible into two main

series on the basis of the position of the fi rst double

bond from the methyl end of the fatty acid chain, the

parent fatty acids being linoleic (C18:2n-6) and α-

linolenic (C18:3n-3) acids. The cholesterol-lowering

effects of dietary PUFA is largely attributable to the

effects of linoleic acid in lowering LDL. Historically,

Intracellular

pool of free

cholesterol

Cholesterol

esters

Cholesterol

esters

LDL receptors Blood LDL-C

Intracellular

pool of free

cholesterol

MUFAs and PUFAs

ACAT

ACAT

Saturated fatty acids

Figure 6.16 Infl uence of dietary fatty

acids on serum cholesterol through

differential effects on free cholesterol and

low-density lipoprotein (LDL) receptor

activity. ACAT, acyl-CoA-cholesterol acyl-

transferase; LDL-C, LDL cholesterol; MUFA,

monounsaturated fatty acid; PUFA, poly-

unsaturated fatty acid.