Impaired receptor biosynthesis

The answer is D. This patient s tests indicate that he has severe hypercholesterolemia and high blood pressure in conjunction with atherosclerosis. The deaths of several of his family members due to heart disease before age 60 suggest a genetic component, ie, familial hypercholesterolemia. This disease results from mutations that reduce production or interfere with functions of the LDL receptor, which is responsible for uptake of LDL-cholesterol by liver cells. The LDL receptor binds and internalizes LDL-choles-terol, delivers it to early endosomes and then recycles back to the plasma membrane to pick up more ligand. Reduced synthesis of apoproteins needed for LDL assembly would tend to decrease LDL levels in the bloodstream, as would impairment of HMG CoA reductase levels, the rate-limiting step of cholesterol biosynthesis. Reduced uptake of bile salts will also decrease cholesterol levels in the blood. 

Cultured fibroblasts from FH individuals synthesize cholesterol at abnormally high levels in the presence of LDLs, compared to normal cells. This activity is linked to the enzyme HMG-CoA reductase, the major regulatory enzyme of cholesterol biosynthesis, which is allosterically inactivated by cholesterol. Cells from FH individuals have an impaired ability to take up cholesterol, via receptor mediated endocytosis, thus requiring endogenous synthesis. LDL levels in the bloodstream remain high, due to lack of uptake. High LDL levels favor oxidation of the components of the LDL and ultimately formation of atherosclerotic plaques. 

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