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CASE FILES: BIOCHEMISTRY
[30.3]
C. The major regulatory enzyme of cholesterol metabolism, P-
hydroxy-P-methylglutaryl-CoA reductase, is regulated by three dis-
tinct mechanisms. The first is phosphorylation by a cAMP dependent
protein kinase. Phosphorylation of P-hydroxy-P-methylglutaryl-CoA
reductase inactivates the enzyme. The other two mechanisms involve
the levels of cholesterol. The degradation of the enzyme is controlled
by cholesterol levels. The half-life of P-hydroxy-P-methylglutaryl-
CoA reductase is regulated by cholesterol levels with high concen-
trations of cholesterol leading to a shorter half-life. The final
regulatory mechanism involves control of the expression of the P-
hydroxy-P-methylglutaryl-CoA reductase gene. High levels of cho-
lesterol lead to a decrease in the mRNA levels coding for
P-hydroxy-P-methylglutaryl-CoA reductase.
[30.4]
E. The statin class of drugs—Lipitor (atorvastatin), Mevacor (lovas-
tatin), and Zocor (simvastatin)—is used to treat hypercholes-
terolemia. This class of drugs lowers cholesterol levels by inhibiting
the biosynthesis of cholesterol. Specifically, these drugs inhibit the
enzyme P-hydroxy-P-methylglutaryl-CoA (HMG-CoA) reductase,
which catalyzes the reaction that converts HMG-CoA to mevalonate.
This is the rate-limiting step of cholesterol biosynthesis.
In addition to the statin drugs which inhibit HMG-CoA reductase
a number of other drugs are used to lower cholesterol levels. The first
are resins which are also referred to as bile acid sequestrants such as
cholestyramine. The resins work by binding to the bile acids followed
by excretion of the resin-bile complex. To make up for the loss of the
bile acids the body converts cholesterol into bile acids thus reducing
the cholesterol levels.
Another type of drug used is the fibrates such as gemfibrozil.
These compounds work by lowering the levels of triglycerides and
increasing the levels of the “good” high-density lipoproteins (HDLs).
Niacin is also effective in lowering cholesterol levels when used in
large doses (more than that required for niacin as a vitamin). Niacin
acts to lower levels of triglycerides and low-density lipoproteins
(LDLs) and increasing the levels of the “good” high-density lipopro-
teins (HDLs).
Drugs such as ezetimibe which inhibit the absorption of choles-
terol in the intestine are effective in lowering cholesterol levels. This
drug is often given in combination with a statin and this combination
therapy is very effective in lowering cholesterol levels.
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