Fig. 5. Sterol derivatives in hedgehog signaling. (A) The hedgehog (Hh) signaling pathway. Hh precursors undergo autocatalytic cleavage to generate a biologically active amino-terminal peptide covalently modified by cholesterol (HhN). Following release from cells, HhN acts on Patched to relieve Smoothened (SMO) repression, leading to the activation of the Gli family of transcription factors. (B) Oxysterols may positively regulate Hh signaling, either via repression of Patched (solid line) or the activation of SMO through as yet unknown mechanisms (dashed line). (C) Vitamin D metabolites negatively regulate SMO. Patched-expressing cells secrete a SMO inhibitor derived from 7-dehydrocholesterol that associates with lipoproteins (solid lines; right panel). In addition to locally synthesized sterols, exogenously derived vitamin D₃ metabolites might also have the potential to affect SMO activity (left panel). These metabolites may enter cells either packaged in lipoprotein particles or complexed with vitamin D binding protein (DBP) via LRPs (dotted lines). Extrac., extracellular; Intrac., intracellular; PM, plasma membrane.