SECTION 19.3
Cholesterol
417
D ep h osp h o-red u ctase kinase
ATP
(inactive)
„___
R ed u ctase kinase
(cA M P-independent)
ADP
p'Khosphatasej^Q
_
, •
D ephospho-H M G -C oA reductase
^
(active)
Phospho-inhibitor protein
^
(active)
P hosp h o-red u ctase kinase
(active)
Phosphatase"
Z
Phospho-H M G -C oA red u ctase
(inactive)
HjO
CAMP -^ -P r o te in
kinase
ADP^
Mg ^
A TP—
-©-■
Dephospho-inhibitor protein
(inactive)
FIGURE 19-11
Regulation of HMG-CoA reductase by phosphorylation-dephosphorylation; phosphorylation leads to loss of
catalytic activity. The two phosphatases are identical and are inhibited by an inhibitor protein that is more active
when phosphorylated by a cAMP-dependent protein kinase. Phosphorylation of reductase kinase is not
cAMP-dependent.
not in enucleated cells, indicating involvement of the
nucleus. The oxygenated sterols are synthesized in mito-
chondria and may repress the HMG-CoA reductase gene
or activate genes for enzymes that degrade the reductase.
A rare familial sterol storage disease,
cerebroten din ous
xanthom atosis,
is
characterized
by
accumulation
of
cholesterol (and its reduced product cholestanol) in
every tissue, especially in brain, tendons, and aorta,
causing progressive neurological dysfunction, tendon
xanthomas, premature atherosclerosis, and myocardial
infarction.
Patients also develop cholesterol gallstones from a
defect in bile acid synthesis. The defect is in the mito-
chondrial C
2 7
-steroid 27-hydroxylase. In these patients,
the reduced formation of normal bile acids, particularly
chenodeoxycholic acid, leads to the up-regulation of the
rate limiting enzyme 7a-hydroxylase of the bile acid syn-
thetic pathway (discussed later). This leads to accumula-
tion of 7a-hydroxylated bile acid intermediates that are
not normally utilized.
The inhibition of cholesterol synthesis by oxygenated
sterols involves the following steps. After synthesis in the
mitochondria, oxygenated sterols in the cytoplasm inhibit
the activation of
sterol regulatory elem ent binding protein s
(SREBPs), eventually leading to suppression of choles-
terol biosynthesis. In cholesterol depleted states, activation
of SREBPs requires participation of the SREBP-cleavage
activating protein and two proteases. The mature SREBPs
are translocated to the nucleus. In the nucleus, SREBPs
function as transcription factors and activate, along with
other factors, several genes by interacting at promoter
sites consisting of a 10-base pair
cis
element known as
sterol regulatory element-1 (SRE-1). Examples of acti-
vated genes include HMG-CoA synthase, HMG-CoA re-
ductase, and low-density lipoprotein (LDL) receptors. The
latter internalizes LDL to provide cholesterol to cells.
HMG-CoA reductase is inhibited competitively by
structural analogues. These compounds are commonly
known as “statins” and are used pharmacologically in
cholesterol reduction which can reduce the risk for
coro-
n ary a rtery d isea se
and stroke (Chapter 20). Statins in-
hibit HMG-CoA reductase at a much lower concentration
(1
fiM)
compared to the
K m
for HMG-CoA (10 /j M).
The structures of clinically effective statins are shown
in Figure 19-12. Lovastatin, simvastatin, and pravas-
tatin are derivatives of naturally occurring fungal prod-
ucts and fluvastatin, atorvastatin and cerivastatin are en-
tirely synthetic compounds. Lovastatin and simvastatin
are inactive lactones that are activated by the liver; oth-
ers are active hydroxy-acids. Naturally occurring statins
are found in a dietary supplement known as cholestin,
which is obtained from rice fermented in red yeast.
In China red yeast rice has been used as a coloring
and flavoring agent. Cholestin’s safety and effectiveness
as hypocholesterolemic agent awaits long-term clinical
studies.
