Inducible Degrader Of the Low-density lipoprotein Receptor (LDLR), IDOL, is an E3 ligase that targets LDLR, very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (apoeR2) for degradation. We have previously demonstrated that IDOL is an evolutionarily conserved regulator of lipid uptake. Furthermore, single nucleotide polymorphisms in IDOL are associated with altered plasma cholesterol levels in humans. Studies have demonstrated a role for IDOL in the brain and liver; however, the importance of IDOL in the regulation of skeletal muscle lipid metabolism remains to be determined.
Here, we utilised genetically modified mouse models to examine the role of IDOL in skeletal muscle lipid metabolism in vivo. Comparison of IDOL fl/fl and IDOL fl/fl-MCK-Cre+/- mice demonstrated that skeletal muscle specific deletion of IDOL was associated with poorer glucose handling as indicated by a glucose tolerance test following either chow or high fat diet. This was observed in the absence of differences in body weight or fat mass. IDOL fl/fl-MCK-Cre+/- mice exhibited an induction of C18:0 ceramide and a concomitant reduction of fibroblast growth factor-21 (FGF-21) mRNA expression in the tibialis anterior (TA). Conversely, ectopic expression of IDOL in C57BL/6J mice via adeno-associated virus (AAV; 1E10) in the TA was associated with a marked increase in FGF-21 mRNA expression compared to the control-treated mice as well as a significant reduction in ceramide accumulation. Enhanced basal glucose uptake was also observed in muscle of IDOL-AAV treated mice. These phenotypes were abolished in the IDOL-AAV treated VLDLR knockout mice, suggesting IDOL regulates glucose metabolism through VLDLR-dependent pathways in skeletal muscle.
Together, these studies suggest that IDOL supresses ceramide accumulation and enhances glucose metabolism in skeletal muscle through increased muscle-derived FGF-21. Further studies are warranted to understand the underlying mechanisms by which IDOL mediates these effects.