| First Author | Nihei W | Year | 2018 |
| Journal | J Lipid Res | Volume | 59 |
| Issue | 11 | Pages | 2181-2187 |
| PubMed ID | 30242108 | Mgi Jnum | J:267199 |
| Mgi Id | MGI:6256584 | Doi | 10.1194/jlr.M089201 |
| Citation | Nihei W, et al. (2018) NPC1L1-dependent intestinal cholesterol absorption requires ganglioside GM3 in membrane microdomains. J Lipid Res 59(11):2181-2187 |
| abstractText | Intestinal cholesterol absorption is a key regulator of systemic cholesterol homeostasis. Excessive dietary cholesterol and its intestinal uptake lead to hypercholesterolemia, a major risk factor for cardiovascular disease. Intestinal cholesterol uptake is mediated by Niemann-Pick C1-like 1 (NPC1L1), a transmembrane protein localized in membrane microdomains (lipid rafts) enriched in gangliosides and cholesterol. The roles of gangliosides, such as monosialodihexosylganglioside (GM3) and its synthesizing enzyme GM3 synthase (GM3S), in NPC1L1-dependent cholesterol uptake have not been examined previously. Here, we examined NPC1L1-dependent cholesterol uptake in a cell model as well as in wild-type and apoE-deficient mice fed normal or high-cholesterol diets. We showed that NPC1L1-dependent cholesterol uptake was impaired in GM3S-deficient cells and that GM3S deficiency promoted resistance to hypercholesterolemia in both wild-type and apoE-deficient mice fed the high-cholesterol but not the normal diet. Our findings suggest that GM3 and related gangliosides are essential for NPC1L1-mediated intestinal cholesterol absorption and are potential targets for hypercholesterolemia therapy. |
