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. 2017 Apr 27;8(24):38099–38112. doi: 10.18632/oncotarget.17485

Figure 7. Model of lysosomal-mediated regulation of cholesterol homeostasis in mTORC1 hyperactive cells.

Figure 7

In physiological conditions, free cholesterol is derived from two main sources: LDLR-mediated uptake and subsequent endosomal/lysosomal processing and SREBP-mediated de novo synthesis. A. In TSC2-deficient cells with mTORC1 hyperactivation, increased cholesterol synthesis is regulated by the transcription factor SREBP. B. Lysosomal inhibition of TSC2-deficient cells with CQ activates compensatory mechanisms for maintaining cholesterol levels, involving both SREBP-mediated activation of the mevalonate pathway and uptake of exogenous lipoprotein uptake via LDLR. In TSC2-deficient (but not TSC2-expressing) cells co-treated with simvastatin, the uptake of exogenous lipoprotein via LDLR is sufficient to over-ride the impact of simvastatin and promote cell survival. C. In TSC2-deficient cells, but not TSC2-expressing cells, combination treatment with CQ and SAR405, a PI3KC3 inhibitor, blocks uptake of exogenous cholesterol esters and inhibits cell survival.