Philippe Boucher, France
UMR CNRS 7021 PhysiologyPresenter of 1 Presentation
Wnt5a promotes endosomal cholesterol trafficking to the ER and protects against atherosclerosis
Abstract
Background and Aims
The Wnt ligand, Wnt5a limits cellular cholesterol accumulation, however, its role in atherosclerosis is unknown.
Methods
To test whether Wnt5a protects against atherosclerosis, we generated SM22Cre+/Wnt5aflox/flox/LDLR-/- mice (smWnt5a-) and littermate controls SM22Cre-/Wnt5aflox/flox/LDLR-/- mice (smWnt5a+) using the Cre/lox system, and studied their vascular phenotype.
Results
We found that mice deleted for Wnt5a in vascular smooth muscle cells (VSMCs) developed atherosclerosis lesions when fed a cholesterol-rich diet. VSMCs accumulated cholesterol in enlarged endosome/lysosome (LELs), and lipofuscin containing vesicles. We identified Wnt5a, as a member of the nutrient/energy/stress sensor, mTORC1 scaffolding complex, which drives lysosomal function and promotes cholesterol trafficking. Treatment of VSMCs with mTORC1 inhibitors or with recombinant Wnt5a decreased activity of mTORC1 allowing endosomal exit of the cholesterol to the ER. This raised ER cholesterol and limited cholesterol accumulation.
Conclusions
Thus, absence of Wnt5a decoupled mTORC1 from variations in LELs sterol levels, and this resulted in accumulation of large intracellular inclusion bodies, large LELs, decreased cholesterol content in the ER, and activation of the sterol regulatory element-binding protein-2 (SREBP-2) a master regulator of cholesterol biosynthesis. These results reveal an unexpected function of the Wnt5a pathway, and provide a conceptually new basis for future drug development to prevent cholesterol accumulation, atherosclerosis, and lysosomal storage diseases.