Uncoupling Nuclear Receptor LXR and Cholesterol Metabolism in Cancer

Liver X receptors (LXRs) are members of the nuclear receptor superfamily of DNA-binding transcription factors and act as sensors of cholesterol homeostasis. Under normal conditions, when intracellular cholesterol concentration increases, cells synthesize oxysterols and activate the LXR transcriptional network to drive cholesterol efflux and reduce cholesterol influx and synthesis. During normal and cancer cell proliferation, there is a net uncoupling between intracellular cholesterol increase and LXR activation resulting from the reduced intracellular oxysterol concentration. This review dissects the novel mechanisms of a previously unrecognized metabolic uncoupling, supporting the activation of the LXR axis as a bona fide therapeutic approach in cancer.