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 for 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.
Using a range of in vitro, ex vivo and in vivo approaches, we aimed to determine the role of IDOL in the regulation of lipid metabolism in skeletal muscle. Ectopic expression of IDOL in C2C12 myotubes was associated with an increased extracellular acidification rate. Interestingly, it was also associated with a 10-fold increase in fibroblasts growth factor (FGF)-21. Similarly, administration of IDOL adeno-associated virus (AAV; 1E10) to the tibialis anterior (TA) was associated with a marked increase in FGF-21 expression compared to the contralateral control-treated TA muscle in mice. A significant reduction in a range of lipid species including several ceramide species was also observed in muscle of IDOL-AAV treated mice. In contrast, comparison of IDOL fl/fl and IDOL fl/fl MCKCre/- 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, in the absence of a phenotype in body weight or percent fat.
Together, these studies establish a role for IDOL in the regulation of skeletal muscle lipid metabolism. Further studies are warranted to understand the underlying mechanisms by which IDOL mediates these effects.