RAB18 deficiency disrupts lipid metabolism and autophagy in mice

Area of Science:

• Molecular Biology
• Genetics
• Metabolomics

Background:

• Rab18 protein, a small G protein, is linked to Warburg Micro Syndrome, a condition causing visual impairment and hind limb weakness.
• The precise cellular and molecular roles of Rab18 in mice remain incompletely elucidated.
• Understanding Rab18's function is critical for deciphering the pathogenesis of related genetic disorders.

Purpose of the Study:

• To investigate the in vivo function of Rab18 in mice.
• To explore the impact of Rab18 deficiency on cellular metabolism and autophagy.
• To elucidate the molecular mechanisms underlying Rab18's role in lipid homeostasis.

Main Methods:

• CRISPR/Cas9 gene editing was employed to generate Rab18 knockout (Rab18-/-) and wild-type (Rab18+/+) mice.
• Phenotypic analysis included assessment of ocular and motor functions (tail suspension test).
• Comprehensive metabolomics and lipid analysis of mouse liver tissues were performed, alongside gene and protein expression studies.

Main Results:

• Rab18-/- mice displayed ocular shrinkage, hind limb weakness, and altered metabolic profiles, including disruptions in lipid, vitamin, and amino acid metabolism.
• Liver analysis revealed increased hepatic lipid droplets, elevated total cholesterol (TC) and triglycerides (TG) levels, and impaired fatty acid release in Rab18-/- mice.
• Rab18 deficiency promoted lipogenic gene/protein expression while inhibiting key autophagy-related genes/proteins, suggesting impaired lipophagy and contributing to lipid accumulation.

Conclusions:

• Rab18 plays a significant role in regulating lipid metabolism and autophagy in mice.
• The absence of Rab18 leads to hepatic lipid accumulation, potentially through the inhibition of lipophagy.
• These findings provide novel insights into the molecular mechanisms of Rab18-associated disorders like Warburg Micro Syndrome.