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PIP4K2A regulates intracellular cholesterol transport through modulating PI(4,5)P2 homeostasis.

PIP4K2A regulates intracellular cholesterol transport through modulating PI(4,5)P2 homeostasis.
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Hu A, Zhao XT, Tu H, Xiao T, Fu T, Wang Y, Liu Y, Shi XJ, Luo J, Song BL,


Hu A, Zhao XT, Tu H, Xiao T, Fu T, Wang Y, Liu Y, Shi XJ, Luo J, Song BL, (click to view)

Hu A, Zhao XT, Tu H, Xiao T, Fu T, Wang Y, Liu Y, Shi XJ, Luo J, Song BL,

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Journal of lipid research 2018 01 20() pii jlr.M082149
Abstract

The transport of LDL-derived cholesterol from lysosomes to peroxisomes is mediated by membrane contacts, which are facilitated by the lysosomal protein synaptotagmin VII and the peroxisomal lipid phosphatidylinositol 4, 5-bisphosphate (PI(4,5)P2). Here, we used RNA interference to search for regulators of PI(4,5)P2 and to study the effects of altered PI(4,5)P2 homeostasis on cholesterol transport. We found that knockdown of phosphatidylinositol 5-phosphate 4-kinase type-2 alpha (PIP4K2A) reduced peroxisomal PI(4,5)P2 levels, decreased lysosome-peroxisome membrane contacts, and increased accumulation of lysosomal cholesterol in human SV-589 fibroblasts. Forced expression of peroxisome-localized, kinase-active PIP4K2A in the knockdown cells reduced cholesterol accumulation, and in vitro addition of recombinant PIP4K2A restored membrane contacts. These results suggest that PIP4K2A plays a critical role in intracellular cholesterol transport by up-regulating PI(4,5)P2 in the peroxisome membrane. Further research into PIP4K2A activity may inform future therapeutic interventions for managing lysosomal storage disorders.

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