100 Introduction to Human Nutrition
that, although the liver has the capacity to synthesize
fatty acids, the amount synthesized by de novo lipo-
genesis is relatively small in humans on a mixed
Western diet. However, the contribution of fatty acids
from this source may increase in conditions associ-
ated with an overproduction of VLDLs, and has been
shown to occur on low-fat, high-carbohydrate diets,
and in metabolic disease.
Metabolic determinants of
lipoprotein metabolism
The metabolism of serum lipoproteins and fate of
their transport lipids is controlled by:
● the physical and chemical characteristics of the
lipoprotein, such as its size and lipid and apopro-
tein content
● the activity of the endothelial LPL and hepatic
lipase (HL), so called because they are attached to
the surface of endothelial cells lining blood vessels
in peripheral tissues, such as adipose tissue and
skeletal muscle, and the liver, respectively
● lipid transfer proteins; cholesteryl ester and phos-
pholipid transfer proteins, (CETP and PLTP
respectively).
● apoproteins that act as activators of enzymes and
ligands for specifi c lipoprotein receptors on the sur-
faces of cells (apoB-100 and apoE as ligands for
the LDLs and remnant receptors in the liver,
respectively)
● the activity of specifi c lipoprotein receptors on cell
surfaces.
Lipoprotein transport is traditionally described in
terms of the forward and reverse transport of choles-
terol. Forward transport encompasses the exogenous
and endogenous pathways, which describes the arrival
of cholesterol in the blood from either the gut or the
liver and carriage back to the liver for processing; the
liver has the unique capacity to secrete cholesterol
either as free cholesterol or as bile acids. Conversely,
reverse transport describes the HDL pathway and the
effl ux of cholesterol out of peripheral tissues back to
the liver. This directionality can be misleading because
each pathway can direct cholesterol back to the liver.
Both the exogenous and endogenous pathways share
a common saturable lipolytic pathway that consists of
a delipidation cascade in which the TAG-rich lipopro-
teins (chylomicrons and VLDLs), after receiving apo-
C (C-II) from HDL, an essential cofactor for the
activation of LPL, are progressively depleted of their
TAG in a stepwise fashion by LPL to become choles-
terol-rich remnants that are removed by specifi c,
high-affi nity receptors found chiefl y in the liver.
Several molecules of LPL may bind to a single chylo-
micron or VLDL particle, although LPL shows greater
affi nity for chylomicrons in preference to VLDL. This
situation leads to competition between these TAG-
rich lipoproteins and provides a mechanism to explain
how VLDL can infl uence the clearance of TAG in the
postprandial period.
Lipolyzed chylomicrons form chylomicron rem-
nants which, during passage through the liver, bind
to specifi c receptors on the surface of hepatocytes that
recognize apoE, an apoprotein that is also acquired at
an early stage from HDLs. Remnant receptors are
maintained at a very high level of activity and are not
downregulated through a feedback mechanism (see
low-density lipoprotein receptor pathway). This is
fortunate, since chylomicron remnants have been
shown to be capable of depositing their cholesterol in
artery walls, thus promoting coronary atherosclerosis.
The secretion of VLDL from the liver is again fol-
lowed by the sequential lipolysis of TAG by LPL and
generation of VLDL remnants or, in this case, the
further lipolysis of these remnants into LDL.
The remnants and LDLs bind to another receptor in
the liver that recognizes both apoE exclusively in
VLDL remnants and apoB-100 in LDLs, namely the
LDL receptor. Approximately 60% of LDL is removed
by the LDL receptor. The remainder is internalized
into cells via scavenger receptors. This latter route has
been associated with the development of atheroscle-
rotic disease.
Whether a VLDL particle is removed as a remnant
or transcends to LDL largely depends on its pedigree,
i.e., its size and lipid composition. Experiments with
radioactively labeled VLDL have shown that larger,
TAG-rich VLDL particles are less likely to be con-
verted into LDL and are removed as partially delipi-
dated VLDL remnants, whereas smaller VLDLs are
precursors of LDL.The low-density lipoprotein
receptor pathway
The incontrovertible link between plasma cholesterol
and CHD is directly responsible for the rapid growth,
and occasional quantum leaps, in our understanding
of cholesterol homeostasis in relation to diet and