Nutrition and Metabolism of Lipids 103of its size, has a much greater potential to infi ltrate
the artery wall and deposit its cholesterol. Even a
moderately raised concentration of serum TAG
(>1.5 mmol/l) may be inversely associated with
reduced HDL cholesterol (<1 mmol/l) and a predomi-
nance of small, dense LDL. This collection of fi ndings
is known as the atherogenic lipoprotein phenotype
(ALP) and is a very common but modifi able source of
increased CHD risk in free-living populations.
Endocrine control of
lipoprotein metabolism
All hormones exert an infl uence on lipoprotein
metabolism. However, with respect to diet and the
control of postprandial lipid metabolism, insulin has
by far the greatest impact. Although classically associ-
ated with carbohydrate metabolism and the uptake of
glucose into cells, the actions of insulin are critical to
the control of postprandial lipid metabolism. Insulin
is secreted in response to the reception of food in the
gut and it:
● stimulates LPL in adipose tissue
● suppresses the intracellular lipolysis of stored TAG
in adipose tissue by inhibiting hormone-sensitive
lipase
● suppresses the release of VLDL from the liver.
Insulin coordinates the lipolysis of dietary TAG and
uptake of NEFA into adipose tissue. It achieves this
by minimizing the release of NEFA from TAG stores
in adipose tissue and TAGs produced in the liver by
suppressing the secretion of VLDL. The sensitivity of
the target tissues – liver, adipose tissue, and, perhaps
to a lesser extent, skeletal muscle – to insulin is critical
to the maintenance of these effects. Failure of insulin
action, insulin resistance, in conditions such as obesity
and diabetes results in dyslipidemia characterized by
an impaired capacity to lipolyze TAG-rich lipopro-
teins (TAG intolerance or enhanced postprandial
lipemia). This effect is compounded by the failure of
insulin to suppress the mobilization of NEFA from
adipose tissue TAG, which increases the fl ux of NEFA
to the liver and stimulates the overproduction of
VLDL (‘portal hypothesis’). The suppression of VLDL
secretion is also abolished so that VLDL is released
into the postprandial circulation and is free to compete
with chylomicrons, augmenting postprandial lipemia
still further. This series of events gives rise to a dys-
lipidemia or ALP, which is found frequently in insulin-
resistant conditions. Insulin also stimulates the
synthesis of cholesterol by activating HMG-CoA
reductase and the activity of LDL receptors, although
the overall effect on cholesterol homeostasis is small
in relation to the control of the LDL pathway described
above.Sex hormones
The effect of sex hormones on serum lipoproteins is
best illustrated by the pronounced differences in lipid
and lipoprotein profi les between adult men and pre-
menopausal women. Men present with higher total
serum and LDL cholesterol, higher serum TAG, and
lower HDL cholesterol concentrations than premeno-
pausal women. This difference in lipid profi les confers
protection against CHD on premenopausal women
so that their CHD risk lags some 10 years behind that
of men of the same age. This applies until estrogen
failure at the menopause, when CHD risk in women
overtakes that of men. Estrogen was the fi rst com-
pound shown to stimulate LDL receptor activity in
cell culture, an effect that not only accounts for lower
LDL levels in women but also the sharp increase in
LDL cholesterol after the menopause, to levels
above those of men. Estrogens also stimulate the pro-
duction of TAG and VLDL, but any adverse effects
must be outweighed by the effi ciency of TAG removal
mechanisms that maintain lower serum TAG levels in
women than in men until the menopause. In addition
to these effects, estrogen selectively inhibits the activ-
ity of HL, which contributes to the HDLs in women.
In direct contrast, the androgenic male hormone tes-
tosterone suppresses LDL receptor activity, raising
LDL cholesterol. It is also a powerful stimulant of HL
activity, and is responsible for lowering HDL choles-
terol in men, most notably in male body builders on
anabolic steroids, in whom serum HDL can be almost
absent.The triacylglycerol hypothesis
Dietary effects on serum cholesterol or LDLs alone
provide an inadequate basis on which to explain the
relationship between diet and CHD within popula-
tions. The ability of humans to protect themselves
against an overaccumulation of cholesterol in their
vascular system through nutritional changes depends
to a much greater extent on increasing the effi ciency
of the HDL pathway and utilization of TAG-rich
lipoproteins. The latter represent the precursors of