Niemann-Pick C1-Like 1 (NPC1L1) Inhibition and Cardiovascular Diseases

Abstract

Circulating levels of cholesterol derive 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 amino-ß-lactam ezetimibe derivatives have been synthesized and their efficacy to inhibit NPC1L1 protein and decrease plasma cholesterol levels is under evaluation.

Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake

“…Our structures show that the cholesterol molecule could trigger the formation of the structural cluster composed of CLR-6, PS-like molecule, and Loops 3-4 and 7-8, while binding with EZE would disrupt this cluster. Because EZE is a clinical drug used to reduce intestinal cholesterol absorption by targeting NPC1L1 ( 35 ), it is thereby reasonable to postulate that the SSD structural cluster is critical for the cellular cholesterol uptake mediated by the human NPC1L1. To test this hypothesis, we generated NPC1L1 variants, in which some residues involved in the interactions within the cluster were mutated, including L649R, L649R-Y654A, G652A-S653A, and L827F-L828A ( Fig.…”

Recent Molecular Mechanisms and Beneficial Effects of Phytochemicals and Plant-Based Whole Foods in Reducing LDL-C and Preventing Cardiovascular Disease

“…Afterward, CEs and TG, under the action of MTTP, form chylomicrons, which are then secreted into the lymphatic system [ 72 ]. Studies have reported that inhibition of intestinal cholesterol absorption effectively lowered the plasma LDL-C level [ 73 ] and reduced the risk of CVD [ 74 ]. Thus, it is necessary to block excessive absorption of cholesterol from the diet and bile [ 75 ].…”

Strategies for the use of nonstatin therapies

“…Ezetimibe reduces intestinal uptake of dietary and biliary cholesterol by inhibiting the interaction with the Niemann-Pick C1-like protein 1 (NPC1L1) [30]. Consequently, the delivery of diet cholesterol to the liver is reduced, thus favouring the increase of hepatic LDLR expression and reducing LDL-C plasma levels.…”