184. Free cholesterol can affect cholesterol metabolism in the body by inhibiting cholesterol biosynthesis. By which step free cholesterol can inhibit its biosynthesis?

Answer: The major regulatory enzyme of cholesterol metabolism, β-hydroxy-β-methylglutaryl-CoA reductase, is regulated by three distinctmechanisms. The first is phosphorylation by a cAMP dependent protein kinase. Phosphorylation of β -hydroxy- β -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 β–hydroxy-β-methylglutaryl-CoA reductase is regulated by cholesterol levels with high concentrations of cholesterol leading to a shorter half-life. The final regulatory mechanism involves control of the expression of the β-hydroxy-β-methylglutaryl-CoA reductase gene. High levels of cholesterol lead to a decrease in the mRNA levels coding for β-hydroxy-β-methylglutaryl-CoA reductase.

185. A patient presents in your office with very high levels of serum cholesterol. He states that he has tried to follow the diet and exercise regimen you gave him last year. You decide that this patient would benefitfrom a drug such as Lipitor (atorvastatin). Wich class of drugs is effective in treating hypercholesterolemia because it has what effect?

Answer: The statin class of drugs – Lipitor (atorvastatin), Mevacor (lovastatin), and Zocor (simvastatin) – is used to treat hypercholesterolemia. This class of drugs lowers cholesterol levels by inhibiting the biosynthesis of cholesterol. Specifically, these drugs inhibit the enzyme β-hydroxy-β-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 lipoproteins (HDLs). Drugs such as ezetimibe which inhibit the absorption of cholesterol 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.