RAB18 deficiency disrupts lipid metabolism and autophagy in mice
Description
Mutation of the small G protein member RAB18 can lead to Warburg Micro Syndrome, characterized clinically by visual impairment and hind limb weakness. However, the cellular and molecular functions of RAB18 in mice are not fully understood. We obtained C57BL/6J Rab18-/+ mice by using CRISPR/Cas9 technology. The Rab18-/+ mice were mated to produce 3 Rab18+/+ and 3 Rab18-/- mice, which were 1 male and 2 female. Our Rab18-/- mice exhibit hind limb weakness and exhibit grip/curling when tail suspended. Through metabolomics analysis, we found that Rab18 knockout affects lipid, vitamin, and amino acid metabolism while also impacting the autophagy signaling pathway. Lipid analysis of mouse liver revealed that Rab18 knockout impaired fatty acid release. Interestingly, Rab18 knockout promoted the expression of lipogenic genes and proteins but did not affect the expression of lipolytic genes and proteins. Since lipophagy, involved in lipid droplet breakdown, plays a key role, we found that Rab18 knockout inhibited the expression of liver autophagy-related genes and proteins. In summary, our results suggest that Rab18 plays a role in autophagy in mice, likely contributing to mechanisms of lipid accumulation.