RAB18 deficiency disrupts lipid metabolism and autophagy in mice

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.

小G蛋白成员RAB18的突变可能导致Warburg微综合征，其临床特征表现为视力障碍和后肢无力。然而，RAB18在小鼠中的细胞和分子功能尚不明确。我们利用CRISPR/Cas9技术获得了C57BL/6J Rab18-/+小鼠。将Rab18-/+小鼠进行交配，产生了3只Rab18+/+小鼠和3只Rab18-/-小鼠，其中1只为雄性，2只为雌性。我们的Rab18-/-小鼠表现出后肢无力，并在尾巴悬挂时出现握持/卷曲现象。通过代谢组学分析，我们发现RAB18敲除影响了脂质、维生素和氨基酸的代谢，同时也影响了自噬信号通路。小鼠肝脏的脂质分析显示，RAB18敲除损害了脂肪酸的释放。有趣的是，RAB18敲除促进了脂生成基因和蛋白的表达，但并未影响脂解基因和蛋白的表达。鉴于脂噬作用，在脂滴分解中发挥关键作用，我们发现RAB18敲除抑制了肝脏自噬相关基因和蛋白的表达。总之，我们的研究结果提示RAB18在小鼠自噬过程中发挥作用，可能有助于脂质积累机制的解析。