Physiological role of hepatic NPC1L1 in human cholesterol and lipoprotein metabolism: New perspectives and open questions

Philip N Howles,David Y Hui

doi:10.1194/jlr.e031823

Abstract

The importance of the cholesterol transporter Niemann-Pick C1 like protein 1 (NPC1L1)in the small intestine for efficient absorption of cholesterol is well documented and its physiological importance is clear (1). Similarly, the drug ezetimibe (Zetia™), which blocks function of this transporter, reduces plasma cholesterol, primarily LDL, by dramatically reducing intestinal absorption of dietary and biliary cholesterol (2). There are controversies about the exact mechanism by which NPC1L1 functions: whether the protein is on the apical cell membrane or intracellular vesicles or both (3–5), and whether ezetimibe directly blocks NPC1L1 or interrupts its association with other proteins in the sterol absorption and transport pathway (6–8). Nevertheless, it is now accepted that this protein is the key player in sterol absorption, although other transporters may play ancillary roles (9, 10).

Highlights

The importance of the cholesterol transporter NiemannPick C1 like protein 1 (NPC1L1)in the small intestine for efficient absorption of cholesterol is well documented and its physiological importance is clear [1]
NPC1L1 is abundant in human liver, its physiological role with regard to hepatic cholesterol and lipoprotein metabolism is less clear
While low NPC1L1 expression was found in one cohort of gallstone disease patients [13], ezetimibe has not been found to increase this risk in the SHARP trial [14] and there is some limited evidence that it may decrease risk due to the overriding increase in cholesterol excretion [15]

Summary

Introduction

The importance of the cholesterol transporter NiemannPick C1 like protein 1 (NPC1L1)in the small intestine for efficient absorption of cholesterol is well documented and its physiological importance is clear [1]. This lack of information reflects, in large part, species differences: mice, the most widely used animal model for NPC1L1 studies as well as cholesterol metabolism, do not express NPC1L1 in liver. Transgenic mice with liver-specific overexpression (20 times) of human NPC1L1 were found to have reduced biliary cholesterol secretion [11].

Results

Conclusion