Importance of γ-secretase in the regulation of liver X receptor and cellular lipid metabolism

Presenilins (PS) are the catalytic components of gamma-secretase complexes that mediate intramembrane proteolysis. Mutations in the PS genes are a major cause of familial early-onset Alzheimer disease and affect the cleavage of the amyloid precursor protein, thereby altering the production of the amyloid beta-peptide. However, multiple additional protein substrates have been identified, suggesting pleiotropic functions of gamma-secretase. Here, we demonstrate that inhibition of gamma-secretase causes dysregulation of cellular lipid homeostasis, including up-regulation of liver X receptors, and complex changes in the cellular lipid composition. Genetic and pharmacological inhibition of gamma secretase leads to strong accumulation of cytoplasmic lipid droplets, associated with increased levels of acylglycerols, but lowered cholesteryl esters. Furthermore, accumulation of lipid droplets was augmented by increasing levels of amyloid precursor protein C-terminal fragments, indicating a critical involvement of this y-secretase substrate. Together, these data provide a mechanism that functionally connects gamma-secretase activity to cellular lipid metabolism. These effects were also observed in human astrocytic cells, indicating an important function of gamma-secretase in cells critical for lipid homeostasis in the brain.