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Encyclopedia of Physical Science and Technology EN008C-380 June 29, 2001 16:42

652 Lipoprotein/Cholesterol Metabolism

ER membrane and has several transmembrane domains
that are necessary in order for cholesterol to stimulate the
degradation of the protein.

IX. HOW DO STEROLS REGULATE
GENE EXPRESSION?

Cholesterol regulates its own formation by inhibiting the
transcription of several genes in the cholesterol pathway,
most notably HMG-CoA synthase and HMG-CoA reduc-
tase. For many years it was also known that polyunsatu-
rated fats decrease the level of cholesterol synthesis. Now
we know how these regulatory events occur.
The transcription of the cholesterol-regulated genes is
regulated by a regulatory region that is upstream (before
thetranscriptionalstartsite)ofthesegenes.AspecialDNA
sequence termed sterol responsive element (SRE) deter-
mines the responsiveness of these genes to regulation by
cholesterol. How does cholesterol inhibit the transcription
of genes with SREs?
A transcription factor that binds to SREs is termedsterol
regulatory element binding protein (SREBP). This protein
turns on the transcription of genes with SREs in front of
them, thus is a positive transcription factor.
SREBP is found in the nuclear and endoplasmic retic- FIGURE 11 Transcriptional regulation of sterol-responsive
ulum membrane in an inactive form. To be activated, it genes. A transcription factor termed sterol regulatory element
must be cleaved from the membrane and released so that binding protein (SREBP) binds to the SREs and enhances tran-
scription. However, the SREBP is held captive bound to the endo-
it can enter the nucleus and turn on transcription. The
plasmic reticulum membrane. Only when it is released by prote-
key to cholesterol regulation is that cholesterol (or more olytic cleavage does it travel to the nucleus, where it regulates
likely, a metabolite of cholesterol) inhibits this cleavage sterol-responsive genes. The protein traverses the membrane
event. The “sensing” of cholesterol is carried out by an- twice and is cleaved by the successive actions of two proteases.
other protein, sterol cleavage activated protein (SCAP), The proteolysis step occurs in the Golgi. Transport of SREBP to
the Golgi requires a second protein, SCAP. The transport step is
a protein that binds to SREBP. In sterol-depleted cells,
inhibited by cholesterol through a sterol-sensing function of SCAP.
SCAP escorts SREBP from the ER to the Golgi, where it Thus, cholesterol regulates gene expression by controlling the ac-
is activated by proteolytic cleavage. This transport step is tivation of a membrane-bound transcription factor, SREBP.
blocked by sterols. Interestingly, unsaturated fatty acids
also inhibit SREBP activation, thus explaining how they
inhibit cholesterol synthesis (Fig. 11). Section XVI) is also associated with increased levels of
The LDL receptor is also regulated by an SRE. This VLDL. This might be a consequence of insulin-mediated
explains why cholesterol downregulates the activity of the stimulation of SREBP expression.
LDL receptor. Many genes in fatty acid and triglyceride Patients lacking the LDL receptor do not accumulate
synthesis are regulated by SREs. The list is growing; thus chylomicron remnants in the bloodstream. Since chylomi-
the importance of SREBP in physiology will be enlarged cron remnant clearance is mediated by apo-E, it has been
in the future. postulated that a separate receptor is responsible for chy-
The expression of SREBP is enhanced by insulin. This lomicron remnant clearance, a receptor that, in contrast to
helps to understand how insulin promotes lipogenesis the LDL receptor, binds to apo-E, but not to apo-B100.
through through global activation of expression of numer- Several additional members of the LDL receptor family
ous lipogenic enzymes. In some individuals on high carbo- have been identified (Table V). The first of these, the LRP,
hydrate diets, plasma VLDL levels rise, a consequence of participates in chylomicron remnant clearance and plays a
an abnormally high rate of de novo lipogenesis. The hy- major role in that process when the LDL receptor is absent
perinsulinemia that accompanies insulin resistance (see or dysfunctional.