Fig. 5

The relationship between lipids and hedgehog signaling. a Regulation of canonical hedgehog signaling by lipids. Smoothened (SMO) is the nexus of hedgehog pathway regulation by lipids. Cholesterol, oxysterols, and phosphatidylinositol-4-phosphate (PI(4)P) are SMO activators, whereas the plant sterol cyclopamine and a distinct class of B-ring oxysterols, DHCEO (7DHC, 3β,5α-dihydroxycholest-7-en-6-one) inhibit SMO. PTCH prevents activation of hedgehog signaling by restricting the access of cholesterol and PI(4)P to SMO while also inhibiting the synthesis of the latter lipid molecule. PI(4)P also prevents the entry of negative regulators of hedgehog signaling, TULP3 and GPR161, to the primary cilium. In hepatocytes, downstream of SMO full-length activated GLI was reported to repress the lipogenic transcriptional program (dashed inhibitory arrow) but the mechanism is unclear. GLIR GLI repressor, GLIFL full-length GLI. b Non-canonical signaling via AMPK in muscle and brown fat. AMPK is activated by SMO via liver kinase complex B1 (LKB1) and calcium/calmodulin-dependent kinase kinase 2 (CAMKK2). In turn, adenosine monophosphate kinase (AMPK) represses cholesterol production directly by inhibition of HMG-CoA reductase (HMGCR) and sterol regulatory element-binding protein 2 (SREBP2) and indirectly through mTORC1 inhibition. In this context cyclopamine was reported to act as a partial agonist of SMO, but whether cholesterol activates SMO has not been tested (question mark above arrow). Lipid/sterol molecules and lipogenic transcription factors are shown in red. Arrows indicate activation (arrowhead) or inhibition (orthogonal bars), except for the arrow from PI to PI(4)P, which indicates an enzymatic step