Introduction to Human Nutrition

Nutrition and Metabolism of Lipids 101

disease, the most prolifi c of which was the discovery
of the LDL receptor pathway by the Nobel Prize
winners Goldstein and Brown (1977) (Figure 6.8). All
cells, most notably those in the liver, have a highly
developed and sensitive mechanism for regulating
intracellular and intravascular levels of cholesterol.
Cells in the liver synthesize approximately 500 mg of
cholesterol a day and, although they can import the
same quantity from the blood in the form of LDL, in
the complete absence of LDL, cells could theoretically
manufacture suffi cient cholesterol to meet their met-
abolic needs. However, when stressed, cells will always
import cholesterol in preference to synthesizing it
themselves as the former process takes less energy.
Cells acquire cholesterol from the blood by the uptake
and degradation of LDL particles. As the requirement
for free cholesterol increases within the cell, it increases
its production and thus activity of LDL receptors, so
that more LDL is extracted from the blood, lowering
blood cholesterol. Conversely, if the cell becomes
overloaded with cholesterol, it senses that it requires
less cholesterol and produces fewer LDL receptors,
causing blood cholesterol to increase. Since the pro-
duction of LDL receptors is regulated by the intracel-
lular level of free cholesterol, anything that increases
free cholesterol within the cell will inadvertently lower
blood LDL cholesterol. Intracellular free cholesterol
represses the activity of a sterol regulatory element
binding protein (SREBP), a positive nuclear tran-
scription factor that promotes the transcription of the
LDL receptor gene when free cholesterol levels fall.

The metabolic effects of intracellular free cholesterol

are:

● it decreases the production of LDL receptors via

SREBP

● it inhibits the synthesis of cholesterol by the

enzyme 3-hydroxy-3-methylglutaryl (HMG)-CoA

reductase

● it increases the re-esterifi cation of cholesterol for

storage as cholesterol esters.

Goldstein and Brown were aided in the discovery

of the LDL receptor by studying a condition known

as familial hypercholesterolemia, a genetic abnormal-

ity in the LDL receptor gene that produces defects in

the LDL receptor pathway and considerably elevated

blood cholesterol concentrations in early life (15–

20 mmol/l) and premature cardiovascular disease.

They also initiated pioneering studies on the infl u-

ence of dietary fats on the activity of the LDL pathway,

which led to a widely accepted explanation for

the cholesterol-raising properties of saturated fatty

acids.

Reverse cholesterol transport (high-density

lipoprotein pathway)

The removal of cholesterol from tissues back to the

liver via HDLs represents the only route of elimina-

tion for cholesterol from the body. This physiological

role of HDLs explains, in part, the cardioprotective

effects of these lipoproteins, as indicated by a strong

inverse relationship between serum HDL cholesterol

Free cholesterol

HMG-CoA reductase

Y

Y

Y

Y

Acetate

Y

Transcription LDL receptor gene 

Y

Y

Transcription

factor

Liver cell

LDL receptor protein

LDL

receptors



LDL

Serum LDL

N-SREBP

Figure 6.8 Low-density lipoprotein (LDL)

receptor pathway. HMG-CoA, 3-hydroxy-3-

methyl-glutaryl-coenzyme A; SREBP, sterol

regulatory element binding protein.