Heart disease represents the most common cause of death in the United States. A major risk factor for heart disease is elevated levels of low-density lipoprotein (LDL) cholesterol. Increased LDL cholesterol concentration may occur due to a heritable condition known as familial hypercholesterolemia (FH), which is typically inherited as an autosomal trait. Hundreds of causative mutations for FH have been identified; such mutations most commonly reduce or eliminate the function of the LDL receptor (LDLR), a cell surface protein required for LDL binding, internalization, and transport.
The LDL transport pathway proceeds as follows:
1. Plasma LDL is bound by LDLR at the cell surface.
2. Bound LDL cargo is endocytosed and ultimately incorporated into lysosomes, where LDL dissociates from LDLR.
3. LDL is processed and released from lysosomes into the cell cytoplasm as cholesterol esters.
4. The released cholesterol leads to suppression of cholesterol synthesis via inhibition of HMG-CoA reductase, the enzyme catalyzing the first step in the cholesterol biosynthetic pathway.
While healthy individuals generally exhibit serum cholesterol concentrations ranging between 120 and 180 mg/dL, those heterozygous for the FH trait have significantly elevated cholesterol levels (250 to 500 mg/dL), and FH homozygotes display concentrations that are dangerously high (600 to 1000 mg/dL). Statins, the best-selling class of pharmaceuticals in production, are an effective treatment for FH in heterozygous individuals. However, statins exhibit low efficacy among FH homozygotes, who normally die before the age of 20.
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