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ARAP2 promotes GLUT1-mediated basal glucose uptake through regulation of sphingolipid metabolism

Aditi Chaudhari ; Liliana Håversen ; Reza Mobini ; Linda Andersson ; Marcus Ståhlman ; Emma Lu ; Mikael Rutberg ; Per Fogelstrand ; Kim Ekroos ; Adil Mardinoglu (Institutionen för biologi och bioteknik, Systembiologi) ; Malin Levin ; Rosie Perkins ; Jan Borén
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids (1388-1981). Vol. 1861 (2016), 11, p. 1643-1651.
[Artikel, refereegranskad vetenskaplig]

Lipid droplet formation, which is driven by triglyceride synthesis, requires several droplet-associated proteins. We identified ARAP2 (an ADP-ribosylation factor 6 GTPase-activating protein) in the lipid droplet proteome of NIH-3T3 cells and showed that knockdown of ARAP2 resulted in decreased lipid droplet formation and triglyceride synthesis. We also showed that ARAP2 knockdown did not affect fatty acid uptake but reduced basal glucose uptake, total levels of the glucose transporter GLUT1, and GLUT1 levels in the plasma membrane and the lipid micro-domain fraction (a specialized plasma membrane domain enriched in sphingolipids). Microarray analysis showed that ARAP2 knockdown altered expression of genes involved in sphingolipid metabolism. Because sphingolipids are known to play a key role in cell signaling, we performed lipidomics to further investigate the relationship between ARAP2 and sphingolipids and potentially identify a link with glucose uptake. We found that ARAP2 knockdown increased glucosylceramide and lactosylceramide levels without affecting ceramide levels, and thus speculated that the rate-limiting enzyme in glycosphingolipid synthesis, namely glucosylceramide synthase (GCS), could be modified by ARAP2. In agreement with our hypothesis, we showed that the activity of GCS was increased by ARAP2 knockdown and reduced by ARAP2 overexpression. Furthermore, pharmacological inhibition of GCS resulted in increases in basal glucose uptake, total GLUT1 levels, triglyceride biosynthesis from glucose, and lipid droplet formation, indicating that the effects of GCS inhibition are the opposite to those resulting from ARAP2 knockdown. Taken together, our data suggest that ARAP2 promotes lipid droplet formation by modifying sphingolipid metabolism through GCS.

Nyckelord: ARAP2; Glucosylceramide synthase; GLUT1; lipid droplets; triglyceride synthesis

Denna post skapades 2016-08-31. Senast ändrad 2017-09-14.
CPL Pubid: 241028


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Institutionen för medicin, avdelningen för molekylär och klinisk medicin (GU)
Institutionen för biologi och bioteknik, Systembiologi


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