Circulating levels of cholesterol are derived from either endogenous production or intestinal absorption
of dietary and biliary cholesterol. Niemann-Pick C1-Like 1 (NPC1L1) is a transmembrane protein
that plays a key role in the intestinal absorption of cholesterol by facilitating its uptake through vesicular endocytosis.
NPC1L1 is the molecular target of ezetimibe which binds its extracellular loop and inhibits sterol
absorption without affecting the absorption of other molecules. Ezetimibe significantly reduces plasma levels
of total and low density lipoprotein cholesterol (LDL-C) as monotherapy or when added to statins, the association
with a low dose of statin is of particular interest for patients experiencing statin-related side effects.
The recent results of the IMPROVE-IT study, which evaluated the cardiovascular effect of ezetimibe added to
simvastatin therapy in subjects who had had an acute coronary syndrome and with LDL-C levels within the
recommended range, showed that a further LDL-C lowering reduced the incidence of cardiovascular events.
To date, ezetimibe represents the only inhibitor of NPC1L1 available for clinical use, however, novel aminoß-
lactam ezetimibe derivatives have been synthesized and their efficacy to inhibit NPC1L1 protein and decrease
plasma cholesterol levels is under evaluation.
Keywords: NPC1L1, cholesterol, cholesterol absorption, ezetimibe, LDL-C, cardiovascular disease.
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