The role of Niemann-Pick C1 - Like 1 (NPC1L1) in intestinal sterol absorption

Abstract

The absorption of cholesterol by the proximal small intestine represents a major pathway for the entry of cholesterol into the body pools. This cholesterol is derived primarily from the bile and the diet. In adult humans, typically several hundred milligrams of cholesterol reach the liver from the intestine daily, with the potential to impact the plasma low density lipoprotein-cholesterol (LDL-C) concentration. There are three main phases involved in cholesterol absorption. The first occurs intraluminally and culminates in micellar solubilization of unesterified cholesterol which facilitates its movement up to the brush border membrane (BBM) of the enterocyte. The second phase involves the transport of cholesterol across the BBM by Niemann-Pick C1 Like-1 (NPC1L1), while the third phase entails a series of steps within the enterocyte involving the esterification of cholesterol and its incorporation, along with other lipids and apolipoprotein B48 (apo B48), into nascent chylomicrons (CM). The discovery of the role of NPC1L1 in intestinal sterol transport occurred directly as a consequence of efforts to identify the molecular target of ezetimibe, a novel, potent, and specific inhibitor of sterol absorption that is now widely used in combination therapy with statins for the management of hypercholesterolemia in the general population. Some aspects of the role of NPC1L1 in cholesterol absorption nevertheless remain controversial and are the subject of ongoing research. For example, one report suggests that NPC1L1 is located not in the plasma membrane but intracellularly where it is thought to be involved in cytosolic trafficking of cholesterol, while another concludes that a protein other than NPC1L1 is responsible for the high affinity binding of cholesterol on intestinal BBM. However, other new studies which show that the in vivo responsiveness of different species to ezetimibe correlates with NPC1L1 binding affinity further support the widely held belief that NPC1L1 does facilitate sterol uptake by the enterocyte and is the target of ezetimibe. Added to this is the unequivocal finding that deletion of the gene for NPC1L1 in mice results in a near complete prevention of cholesterol absorption and an accelerated rate of fecal neutral sterol excretion. In summary, the development of ezetimibe and the identification of NPC1L1 as a key player in sterol absorption have taken research on the molecular control of this pathway to an exciting new level. From this it is hoped that we will now be able to determine more precisely what effect, if any, other classes of lipid lowering agents, particularly the statins, might exert on the amount of intestinal cholesterol reaching the liver.

Figure 1

Atherogenic potential of intestinally-derived lipoproteins. This schematic illustrates two mechanisms through which the entry of chylomicron cholesterol (CM-C) into the circulation can potentially play a role in atherosclerotic plaque formation. (1) The uptake of CM-C by the liver can lead to a shift in intrahepatic cholesterol metabolism that in turn causes either a downregulation of low density lipoprotein receptor (LDL-R) activity, or/and an increase in hepatic very low density lipoprotein-cholesterol (VLDL-C) secretion. Either of these events can lead to a rise in the steady-state plasma low density lipoprotein-cholesterol (LDL-C) concentration. (2) Upon entering the circulation, CM’s lose much of their triacylglycerol content, resulting in the formation of a much smaller, cholesterol rich remnant particle (CMr) that can permeate the vessel wall. Ordinarily, CMr particles are rapidly cleared from the circulation by the liver but in Type 2 diabetes and other disorders this clearance rate can be markedly delayed.

Figure 2

Transport of intestinal cholesterol. This illustration summarizes the main steps involved in the uptake of cholesterol (C) from the lumen into the enterocyte, and the intracellular events that lead to the eventual incorporation of the cholesterol into nascent chylomicron (CM) particles. Here, Niemann-Pick C1 Like1 (NPC1L1) is depicted as the brush border membrane sterol transporter that facilitates the uptake of cholesterol and non-cholesterol sterols into the enterocyte. As discussed in the text, some studies suggest that other proteins might perform this function, and that NPC1L1 might instead be located at intracellular sites. Fatty acids (FA), which enter the cell through other mechanisms, are either incorporated into triacylglycerols (TG), or used to form cholesteryl esters (CE) through the action of acyl CoA: cholesterol acyltransferase 2 (ACAT2). Subsequently, the CE, as well as some unesterified cholesterol, along with TG and apolipoprotein B48 (apo B48), are packaged into nascent CM through the action of microsomal triglyceride transfer protein (MTP).