RAB18 confers protection to lipid droplets from lysolipophagy and counters cellular steatosis

Lipid droplet (LD) enlargement is the most conspicuous cellular phenotype of steatotic liver diseases such as NAFLD and NASH. The small GTPase RAB18 localizes to lipid droplets yet its effects on LD dynamics are unknown. We show that RAB18 localizes to LDs dynamically via the acylation cycle in an activity dependent manner. Removal of RAB18 from LDs through acylation cycle inhibition of RNAi-mediated downregulation leads to an increase in LD size, that can be prevented by inhibition of autophagy. We propose a model where RAB18 on LDs decreases the susceptibility of LDs to autophagy by lysosomes, allowing them to exist longer in cells and enabling an even distribution of exogenous lipid load. In the absence of RAB18, fewer LDs survive autophagic removal, and enlarge disproportionately as they absorb the incumbent exogenous lipid load on cells - leading to cellular steatosis. Inhibition of autophagy prevented cellular steatosis in primary human hepatocytes. Finally, mice treated with the autophagy inhibitor chloroquine were resistant to the development of liver steatosis when on a steatogenic diet. The modulation of RAB18 activity and autophagy inhibition represents a promising approach to prevent steatotic liver disease in the clinical setting. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/531838v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@57d8f8org.highwire.dtl.DTLVardef@165ad0aorg.highwire.dtl.DTLVardef@43964corg.highwire.dtl.DTLVardef@140746f_HPS_FORMAT_FIGEXP M_FIG C_FIG One line summaryRAB18 prevents lipid droplet autophagy to distribute lipid load in cells and prevent steatosis.