How does a shortage of LDL receptors cause familial hypercholesterolemia?

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A composite diagram shows the structural formulas, space-filling models, and simplified depictions of lipid molecules including stearic acid and phosphatidylcholine, and how these assemble into a micelle and lipid bilayer, with labels identifying hydrophilic heads and hydrophobic tails. — Lipid Structure and properties of two representative lipids. Both stearic acid (a fatty acid) and phosphatidylcholine (a phospholipid) are composed of chemical groups that form polar “heads” and nonpolar “tails.” The polar heads are hydrophilic, or soluble in water, whereas the nonpolar tails are hydrophobic, or insoluble in water. Lipid molecules of this composition spontaneously form aggregate structures such as micelles and lipid bilayers, with their hydrophilic ends oriented toward the watery medium and their hydrophobic ends shielded from the water.

Familial hypercholesterolemia is an inherited metabolic disease caused by a deficiency or dysfunction of LDL receptors on the surface of cells in the liver and other organs.1

Under normal conditions, these receptors facilitate the uptake of LDL cholesterol from the blood into cells. When these receptors are lacking, LDL cholesterol cannot be properly internalized, leading to its accumulation in the bloodstream. This excess cholesterol eventually deposits on the walls of arteries, a process known as atherosclerosis, which significantly increases the risk of cardiovascular disease and heart attack.1

Furthermore, the condition disrupts internal regulatory processes. Typically, the presence of sufficient intracellular cholesterol triggers feedback inhibition to stop further cholesterol synthesis. Because cells in patients with this condition fail to import enough cholesterol, these enzymes remain active, causing the body to produce excessive amounts of cholesterol, further exacerbating the high levels in the blood.1