Sonic hedgehog (Shh) binds to Ptch1, which abolishes the inhibitory effect of Smoothened (Smo) on hedgehog signaling, resulting in activation of hedgehog signaling and transcription factor Gli. In NAFLD, ballooned hepatocyte-derived Shh stimulates hedgehog signaling in hepatocytes, which produce osteopontin to induce liver macrophage accumulation and NAFLD development. Hedgehog signaling is also activated in hepatic stellate cells, macrophages, and adipose tissues, which promotes NAFLD development and insulin resistance. Blocking hedgehog signaling systemically by the administration of Smo inhibitors suppress the progression of NAFLD and insulin resistance.