GRAF1a is a brain-specific protein promoting lipid droplet clustering and growth and enriched at lipid droplet junctions

Abstract

Lipid droplets are found in all cell types. Normally present at low levels in the brain, they accumulate in tumours and are associated with neurodegenerative diseases. However, little is known about the mechanisms controlling their homeostasis in the brain. We have found that the longest GRAF1 isoform, GRAF1a, is enriched in the brains of neonates. Endogenous GRAF1a is found on lipid droplets in oleic-acid fed primary glial cells. Exclusive localization requires a GRAF1a-specific hydrophobic segment and two membrane-binding regions, a BAR and a PH domain. Overexpression of GRAF1a promotes lipid droplet clustering, inhibits droplet mobility and severely perturbs lipolysis following the chase of fatty acid-overloaded cells. Under these conditions, GRAF1a concentrates at the interface between lipid droplets. Although GRAF1 knockout mice do not show any gross abnormal phenotype, the total lipid droplet volume that accumulates in GRAF1−/− primary glia upon incubation with fatty acids is reduced compared to GRAF1+/+ cells. These results provide additional insights into the mechanisms contributing to lipid droplet growth in non-adipocyte cells, and suggest that proteins with membrane sculpting BAR domains play a role in droplet homeostasis.