TY - JOUR T1 - Importance of γ-secretase in the regulation of liver X receptor and cellular lipid metabolism JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900521 VL - 3 IS - 6 SP - e201900521 AU - Esteban Gutierrez AU - Dieter Lütjohann AU - Anja Kerksiek AU - Marietta Fabiano AU - Naoto Oikawa AU - Lars Kuerschner AU - Christoph Thiele AU - Jochen Walter Y1 - 2020/06/01 UR - https://www.life-science-alliance.org/content/3/6/e201900521.abstract N2 - Presenilins (PS) are the catalytic components of γ-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 β-peptide. However, multiple additional protein substrates have been identified, suggesting pleiotropic functions of γ-secretase. Here, we demonstrate that inhibition of γ-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 γsecretase 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 γ-secretase substrate. Together, these data provide a mechanism that functionally connects γ-secretase activity to cellular lipid metabolism. These effects were also observed in human astrocytic cells, indicating an important function of γ-secretase in cells critical for lipid homeostasis in the brain. ER -