Cholesterol regulates its own formation by inhibiting the
transcription of several genes in the cholesterol pathway,
most notably HMG-CoA synthase and HMG-CoA reductase.
For many years it was also known that polyunsaturated
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
the transcriptional start site) of these genes.AspecialDNA
sequence termed sterol responsive element
the responsiveness of these genes to regulation by
cholesterol. How does cholesterol inhibit the transcription
of genes with SREs?
Atranscription factor that binds to SREs is termed sterol
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 reticulum
membrane in an inactive form. To be activated, it
must be cleaved from the membrane and released so that
it can enter the nucleus and turn on transcription. The
key to cholesterol regulation is that cholesterol (or more
likely, a metabolite of cholesterol) inhibits this cleavage
event. The “sensing” of cholesterol is
carried out by another
protein, sterol cleavage activated protein
a protein that binds to SREBP. In sterol-depleted cells,
SCAP escorts SREBP from the ER to the Golgi, where it
is activated by proteolytic cleavage. This transport step is
blocked by sterols. Interestingly, unsaturated fatty acids
also inhibit SREBP activation, thus explaining how they
inhibit cholesterol synthesis (Fig. 11).
|Figure 11 Transcriptional regulation of sterol-responsive
genes. A transcription factor termed sterol regulatory element
binding protein (SREBP) binds to the SREs and enhances transcription.
However, the SREBP is held captive bound to the endoplasmic
reticulum membrane. Only when it is released by proteolytic
cleavage does it travel to the nucleus, where it regulates
sterol-responsive genes. The protein traverses the membrane
twice and is cleaved by the successive actions of two proteases.
The proteolysis step occurs in the Golgi. Transport of SREBP to
the Golgi requires a second protein, SCAP. The transport step is
inhibited by cholesterol through a sterol-sensing function of SCAP.
Thus, cholesterol regulates gene expression by controlling the activation
of a membrane-bound transcription factor, SREBP.
The LDL receptor is also regulated by an SRE. This
explains why cholesterol downregulates the activity of the
LDL receptor. Many genes in fatty acid and triglyceride
synthesis are regulated by SREs. The list is growing; thus
the importance of SREBP in physiology will be enlarged
in the future.
The expression of SREBP is enhanced by insulin. This
helps to understand how insulin promotes lipogenesis
through through global activation of expression of numerous
lipogenic enzymes. In some individuals on high carbohydrate
diets, plasma VLDL levels rise, a consequence of
an abnormally high rate of de novo lipogenesis. The hyperinsulinemia
that accompanies insulin resistance (see Section XVI) is also associated with increased levels of
VLDL. This might be a consequence of insulin-mediated
stimulation of SREBP expression.
Patients lacking the LDL receptor do not accumulate
chylomicron remnants in the bloodstream. Since chylomicron
remnant clearance is mediated by apo-E, it has been
postulated that a separate receptor is responsible for chylomicron
remnant clearance, a receptor that, in contrast to
the LDL receptor, binds to apo-E, but not to apo-B100.
Several additional members of the LDL receptor family
have been identified (Table V). The first of these, the LRP,
participates in chylomicron remnant clearance and plays a
major role in that process when the LDL receptor is absent
TABLE III Properties of the Apolipoproteins
||Molecular weight (Da)
||Cholesterol, triglyceride transport,
||Triglyceride, cholesterol transport
||Liver, intestine, pancreas, kidney, adrenals, brain
||Liver, macrophages, brain, Adrenal
||Spleen, liver, small intestine, adrenal
||Cholesterol ester transfer
||Liver, testes, brain