Niemann-Pick C1-Like 1 protein: Another target for treatment of dyslipidemia? Evidence from the Myocardial Infarction Genetic Consortium and IMPROVE-IT trials.

Abstract

Listen

Translate article

Absorption of both dietary cholesterol and cholesterol cleared from the liver through biliary secretion contributes substantially to tight control of cholesterol homeostasis. This process is mediated by a specific transporter – Niemann-Pick C1-Like 1 (NPC1L1) protein – localized to the brush border membrane of jejunal enterocytes (Figure 1, Table 1).1 NPC1L1 was first described by Davies and colleagues in 2000 while searching for proteins homologues of human Niemann-Pick type C1 protein (NPC1) – the primary causative protein for Niemann-Pick disease type C1 – that may be involved in subcellular cholesterol trafficking.2,3 Human liver express also NPC1L1, however its physiological significance in hepatocytes remains to be elucidated. Figure 1. The Niemann–Pick C1-like-1(NPC1L1) protein (dark red) is located at the apical membrane of enterocytes and facilitates the uptake of cholesterol across the brush border membrane. In contrast, the ABCG5/G8 transporter (green) promotes the active ... Table 1 Comparison Between NPC1L1 and PCSK9 proteins. Ezetimibe – a potent selective inhibitor of NPC1L1 protein activity5 – has been shown to lower plasma levels of low density lipoprotein cholesterol (LDL-C) by 12% to 20%6–8. It was approved, in 2012, by the Food and Drug Administration (FDA) for the treatment of hypercholesterolemia on the basis of its LDL-C lowering alone, despite lack of data on its effects on clinical end-points such as death, myocardial infarction (MI), or stroke in clinical outcome studies. Ezetimibe failed to slow the progression of carotid intima-media thickness, when added to background statin therapy in patients with familial hypercholesterolemia in the landmark Ezetimibe and Simvastatin in Hypercholesterolemia Enhance Atherosclerosis Regression (ENHANCE) trial, reported in January 200811. Unfortunately these negative results cast a shadow over ezetimibe, although the ENHANCE study was heavily criticized by a significant and unexplained 18-month delay between completion of the study and publication of results. In the latest European Society of Cardiology (ESC) and American Heart Association (AHA) prevention guidelines, the use of ezetimibe alone or in combination is considered a class IIb recommendation.12,13 These results move us to more uncertainty about the benefit of this drug, and stimulated the need for conducting large genetic and clinical studies in order to test the impact of NPC1L1 inhibition on clinical outcome. Data from two large studies have been recently published and reviewed here to determine the clinical efficacy and safety of ezetimibe therapy.