In class, we discussed the hereditary disease familial hypercholesterolemia (FH)

Question

In class, we discussed the hereditary disease familial hypercholesterolemia (FH), which is associated with a deficiency in LDL receptors.

a) Please explain the mechanism underlying the high blood levels of cholesterol in these patients.

b) Would endogenous cholesterol synthesis be increased or decreased in these patients? Please explain your answer.

c) In patients who are homozygous for FH (i.e., both copies of the gene are defective), statin drugs are less effective at lowering blood cholesterol levels than in heterozygous FH patients (i.e., only one copy of the gene is defective). Please explain why. In your answer, you do not need to consider the effect of statins on the regulation of HMG-CoA reductase.

d) Another hereditary mutation exists in the gene that codes for apoB100. In patients, the presence of this mutation leads to a decrease in the affinity of the LDL particle for LDL receptors and increased levels of blood cholesterol. Would statin drugs be an effective treatment for such patients? Why or why not? In your answer, you do not need to consider the effect of statins on the regulation of HMG-CoA reductase

Explanation / Answer

a.) In patients suffering from FH the gene encoding for LDL Receptor is mutated. Due to this mutation LDL(Bad Cholesterol) is not removed resulting in high level of cholesterol in the blood.

b.) Endogenous synthesis of cholesterol is decreased in patients suffering from FH.

Endogenous cholesterol synthesis is carried out via HMG-CoA reductase pathway. Normally, LDL binds to LDL receptors triggering its uptake and digestion. This in turn triggers the synthesis of Cholesterol by HMG-CoA reductase pathway.

But in patients suffering from FH, due to mutation in LDL receptor encoding gene, LDL uptake and digestion is suppressed resulting in less synthesis of cholesterol by HMG-CoA reductase pathway.

c.) The hetrozygous FH Patients have only 1 copy of defective gene. There condition is not as critical as the homozygous one. Patients can be treated by statin medication. The homozygous FH patients have two abnormal copies of defective genes which can cause severe cardiovascular diseases in the childhood. In such critical cases statin is relatively ineffective. These patients usually need to go for liver transplant.

d.) Yes, Statin can be used for the treatment of such patients. It is observed that patients with hetrozygous FH benefit from statin medication but statin does not work effectively in homozygous FH patients.

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