title: Dynamic modification of sphingomyelin in lipid microdomains controls development of obesity, fatty liver, and type 2 diabetes.
abstract: Lipid microdomains or caveolae, small invaginations of plasma membrane, have emerged as important elements for lipid uptake and glucose homeostasis. Sphingomyelin (SM) is one of the major phospholipids of the lipid microdomains. In this study, we investigated the physiological function of sphingomyelin synthase 2 (SMS2) using SMS2 knock-out mice, and we found that SMS2 deficiency prevents high fat diet-induced obesity and insulin resistance. Interestingly, in the liver of SMS2 knock-out mice, large and mature lipid droplets were scarcely observed. Treatment with siRNA for SMS2 also decreased the large lipid droplets in HepG2 cells. Additionally, the siRNA of SMS2 decreased the accumulation of triglyceride in liver of leptin-deficient (ob/ob) mice, strongly suggesting that SMS2 is involved in lipid droplet formation. Furthermore, we found that SMS2 exists in lipid microdomains and partially associates with the fatty acid transporter CD36/FAT and with caveolin 1, a scaffolding protein of caveolae. Because CD36/FAT and caveolin 1 exist in lipid microdomains and are coordinately involved in lipid droplet formation, SMS2 is implicated in the modulation of the SM in lipid microdomains, resulting in the regulation of CD36/FAT and caveolae. Here, we established new cell lines, in which we can completely distinguish SMS2 activity from SMS1 activity, and we demonstrated that SMS2 could convert ceramide produced in the outer leaflet of the plasma membrane into SM. Our findings demonstrate the novel and dynamic regulation of lipid microdomains via conformational changes in lipids on the plasma membrane by SMS2, which is responsible for obesity and type 2 diabetes.
authors.affiliation: Department of Biomembrane and Biofunctional Chemistry, Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan. susumu-m@pharm.hokudai.ac.jp
authors.forename: Susumu
authors.initials: S
authors.lastname: Mitsutake
authors.forename: Kota
authors.initials: K
authors.lastname: Zama
authors.forename: Hazuki
authors.initials: H
authors.lastname: Yokota
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yoshida
authors.forename: Miki
authors.initials: M
authors.lastname: Tanaka
authors.forename: Masaru
authors.initials: M
authors.lastname: Mitsui
authors.forename: Masahito
authors.initials: M
authors.lastname: Ikawa
authors.forename: Masaru
authors.initials: M
authors.lastname: Okabe
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamashita
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takemoto
authors.forename: Toshiro
authors.initials: T
authors.lastname: Okazaki
authors.forename: Ken
authors.initials: K
authors.lastname: Watanabe
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Igarashi
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D021941:Caveolae / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002518:Ceramides / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000528:radiation effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013109:Sphingomyelins / Q000235:genetics / Q000378:metabolism*; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D051242:Caveolin 1; D002518:Ceramides; D004041:Dietary Fats; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D013109:Sphingomyelins; C455440:SGMS1 protein, human; C556686:Sgms1 protein, mouse; D017855:Transferases (Other Substituted Phosphate Groups); C543123:Sgms2 protein, mouse