Niemann-Pick C1-like 1 (NPC1L1) is a crucial polytopic transmembrane protein. It is highly enriched in the apical membrane of small intestine absorptive enterocytes and also expressed in the liver [2]. NPC1L1 is essential for intestinal sterol absorption, mediating extracellular sterol transport across the brush border membrane. It is the molecular target of ezetimibe, a cholesterol absorption inhibitor [2]. It plays a key role in cholesterol metabolism-related pathways, influencing plasma low-density lipoprotein levels and whole-body cholesterol homeostasis [1,3].

In Npc1l1 null mice, there is a significant reduction in the intestinal uptake and absorption of cholesterol and phytosterols. These mice are resistant to diet-induced hypercholesterolemia, and when crossed with apo E null mice, are completely resistant to the development of atherosclerosis [3]. In addition, intestinal gene expression studies in Npc1l1 null mice showed that without NPC1L1, no exogenous cholesterol entered enterocytes, leading to an up-regulation of intestinal and hepatic LDL receptor and cholesterol biosynthetic gene expression [3].

In conclusion, NPC1L1 is a critical regulator in intestinal sterol uptake and whole-body cholesterol homeostasis. Gene-knockout mouse models, like Npc1l1 null mice, have been instrumental in revealing its role in cholesterol-related diseases such as hypercholesterolemia and atherosclerosis. Understanding NPC1L1's function can provide potential targets for treating these diseases [3].

References:

1. Xu, ChongLi, Fu, Fengyang, She, Yuhan, Xu, ChongBo. 2023. NPC1L1 Plays a Novel Role in Nonalcoholic Fatty Liver Disease. In ACS omega, 8, 48586-48589. doi:10.1021/acsomega.3c07337. https://pubmed.ncbi.nlm.nih.gov/38162748/

2. Betters, Jenna L, Yu, Liqing. 2010. NPC1L1 and cholesterol transport. In FEBS letters, 584, 2740-7. doi:10.1016/j.febslet.2010.03.030. https://pubmed.ncbi.nlm.nih.gov/20307540/

3. Davis, Harry R, Altmann, Scott W. 2009. Niemann-Pick C1 Like 1 (NPC1L1) an intestinal sterol transporter. In Biochimica et biophysica acta, 1791, 679-83. doi:10.1016/j.bbalip.2009.01.002. https://pubmed.ncbi.nlm.nih.gov/19272334/