Negative Regulation of Hedgehog Signaling by Liver X Receptors

Abstract

Hedgehog (Hh) signaling is indispensable in embryonic development, and its dysregulated activity results in severe developmental disorders as shown by genetic models of naturally occurring mutations in animal and human pathologies. Hh signaling also functions in postembryonic development and adult tissue homeostasis, and its aberrant activity causes various human cancers. Better understanding of molecular regulators of Hh signaling is of fundamental importance in finding new strategies for pathway modulation. Here, we identify liver X receptors (LXRs), members of the nuclear hormone receptor family, as previously unrecognized negative regulators of Hh signaling. Activation of LXR by specific pharmacological ligands, TO901317 and GW3965, inhibited the responses of pluripotent bone marrow stromal cells and calvaria organ cultures to sonic Hh, resulting in the inhibition of expression of Hh-target genes, Gli1 and Patched1, and Gli-dependent transcriptional activity. Moreover, LXR ligands inhibited sonic Hh-induced differentiation of bone marrow stromal cells into osteoblasts. Elimination of LXRs by small interfering RNA inhibited ligand-induced inhibition of Hh target gene expression. Furthermore, LXR ligand did not inhibit Hh responsiveness in mouse embryonic fibroblasts that do not express LXRs, whereas introduction of LXR into these cells reestablished the inhibitory effects. Daily oral administration of TO901317 to mice after 3 d significantly inhibited baseline Hh target-gene expression in liver, lung, and spleen. Given the importance of modulating Hh signaling in various physiological and pathological settings, our findings suggest that pharmacological targeting of LXRs may be a novel strategy for Hh pathway modulation.

Sonic Hedgehog Signaling in the Lung. From Development to Disease

“…Certain corticosteroids interact with SMO but it is not clear if this occurs with pharmacologic concentrations achieved (24). Liver X receptor (LXR) agonists appear to inhibit HH pathway activation and the blockade can be overcome by direct activation of SMO (25). Finally, to study loss-of-function a genetic approach can be taken using mice, which carry either germ line mutations or conditional alleles for the HH pathway members (for references see main review).…”

Hormonal modulators of glial ABCA1 and apoE levels

“…Immortalized LXR double-knockout (LXR ␣ Ϫ /LXR ␤ Ϫ ) and LXR ␣ -expressing (LXR ␣ +) mouse embryonic fi broblasts (MEF) have been described ( 44 ). Astrocytes derived from human apoE3 or apoE4 knock-in mice that were immortalized by SV40 T antigen were obtained from Dr. David Holtzman ( 45 ).…”

Activation of Liver X Receptors Inhibits Hedgehog Signaling, Clonogenic Growth, and Self-Renewal in Multiple Myeloma

“…Oxysterols are oxidized cholesterol molecules capable of both activating and inhibiting Hh signaling (18–20). Specific oxysterols may activate the Hh pathway by directly interacting with SMO through a putative sterol-sensing domain (18, 21).…”