460 Hepatic Steatosis Causes the Dysfunction of Autophagy in NAFLD Patients

triglycerides, and CARS microscopy. In contrast, GDC-0449 treatment significantly attenuated FFC diet-induced liver injury as manifest by reduced plasma ALT values and hepatic TUNEL positive cells. Consistent with a reduction in tissue injury, GDC-0449 normalized FFC diet-induced mRNA levels of TNF-alpha, IL-1beta, monocyte chemotactic protein-1 and a variety of macrophage markers to the levels of mice on chow diet and prevented accumulation of galectin-3 (a macrophage marker) positive cells in the liver. Furthermore, GDC-0449 therapy of FFC diet-fed mice abrogated mRNA upregulation of collagen 1a1, alpha-smooth muscle actin and osteopontin in the liver, and decreased hepatic collagen deposition to values of mice on chow diet as quantified by Sirius red staining and second harmonic generation microscopy of frozen sections using a two photon confocal microscope. GDC-0449 treatment also abolished FFC-diet induced hepatic expression of death receptor TRAIL-R2, but not FAS nor TNFR1. FCC diet fed mice, but not chow fed animals, underwent significant liver injury following treatment with a TRAIL agonist. TRAIL-mediated injury in the FCC diet fed mice was reduced by pre-treatment with GDC-0449. In conclusion, inhibition of hedgehog signaling with GDC-0449 appears to reduce TRAIL-mediated liver injury in a nutrient excess model of NASH, thereby attenuating hepatic inflammation and fibrosis. We speculate that hedgehog signaling inhibition maybe salutary in human NASH.