NPC1L1-mediated cholesterol uptake

Dietary cholesterol is taken up into enterocytes from the gut lumen in a reaction mediated by plasma membrane-associated NPC1L1 protein. This role for NPC1L1 was first observed in studies of a mouse model system (Altman et al. 2004). Subsequent studies of human cultured cells confirmed the participation of NPC1L1 in cholesterol transport across membranes but suggested that this transport process might not be a major factor in dietary cholesterol uptake (Davies et al. 2005). Detailed studies in Maden-Darby canine kidney cells, both mediated by endogenous (canine) NPC1L1 and by overexpressed human protein, indicate a major role for NPC1L1 in the uptake of extracellular cholesterol. These studies have also shown that ezetimibe binds both human and canine proteins and renders them incapable of mediating cholesterol uptake. The molecular mechanisms of cholesterol transport and ezetimibe inhibition, however, remain unclear (Weinglass et al. 2008).

膳食胆固醇通过肠上皮细胞从肠腔中摄取，该过程由质膜相关NPC1L1蛋白介导的相互作用所调控。NPC1L1所扮演的角色首先在Altman等人（2004年）对小鼠模型系统的研究中得以观察。随后，对人类培养细胞的研究证实了NPC1L1在跨越细胞膜的胆固醇转运中的作用，但亦指出该转运过程可能并非膳食胆固醇摄取的主要因素（Davies等人，2005年）。在Maden-Darby犬肾细胞中进行的详细研究，无论是通过内源性（犬类）NPC1L1还是通过过表达的人源蛋白介导，均表明NPC1L1在摄取细胞外胆固醇中起着主要作用。这些研究还揭示了ezetimibe能够与人类和犬类蛋白结合，并使其无法介导胆固醇的摄取。然而，胆固醇转运的分子机制以及ezetimibe的抑制作用仍尚不明确（Weinglass等人，2008年）。