2. Academic Validation
  3. NPC1L1-dependent intestinal cholesterol absorption requires ganglioside GM3 in membrane microdomains

NPC1L1-dependent intestinal cholesterol absorption requires ganglioside GM3 in membrane microdomains

  • J Lipid Res. 2018 Nov;59(11):2181-2187. doi: 10.1194/jlr.M089201.
Wataru Nihei 1,  Masakazu Nagafuku 1,  Hirotaka Hayamizu 1,  Yuta Odagiri 1,  Yumi Tamura 1,  Yui Kikuchi 1,  Lucas Veillon 1 2,  Hirotaka Kanoh 1,  Kei-Ichiro Inamori 1,  Kenta Arai 3,  Kazuya Kabayama 3,  Koichi Fukase 3,  Jin-Ichi Inokuchi 4
Affiliations

Affiliations

  • 1 Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Japan.
  • 2 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • 3 Laboratory of Natural Product Chemistry, Department of Chemistry, Osaka University, Toyonaka, Japan.
  • 4 Division of Glycopathology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Japan [email protected].
PMID: 30242108 DOI: 10.1194/jlr.M089201
Abstract

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.

Keywords

Niemann-Pick C1-like 1; cholesterol absorption; gangliosides; hypercholesterolemia; lipid transport; monosialodihexosylganglioside.

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