期刊
JOURNAL OF LIPID RESEARCH
卷 59, 期 11, 页码 2181-2187出版社
ELSEVIER
DOI: 10.1194/jlr.M089201
关键词
gangliosides; monosialodihexosylganglioside; cholesterol absorption; hypercholesterolemia; lipid transport; Niemann-Pick C1-like 1
资金
- Ministry of Education, Culture, Sports, Science and Technology Research [16H04767]
- Mizutani Foundation for Glycoscience
- Takeda Science Foundation
- Fugaku Trust for Medicinal Research
- Naito Foundation
- Ono Medical Research Foundation
- Uehara Memorial Foundation
- Ministry of Education, Culture, Sports, Science and Technology-supported Program for the Strategic Research Foundation at Private Universities
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.
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