RESUMEN
BACKGROUND & AIM: TNF-related apoptosis-inducing ligand (TRAIL) and its cognate receptor(s) are upregulated in human and murine nonalcoholic steatohepatitis (NASH). However, the consequence of this enhanced expression on NASH pathogenesis remains unclear. TRAIL may either accentuate liver injury by promoting hepatic steatosis and inflammation, or it may mitigate the disease process by improving systemic insulin resistance and averting hepatic fibrosis. Herein, we investigated the role of TRAIL in an obesity-induced murine model of NASH. METHODS: C57BL/6 wild-type (WT) mice and Trail-/- mice were placed on a 20-week standard chow or FFC (high fat, fructose, and cholesterol) diet which induces obesity, insulin resistance and NASH. Metabolic phenotype, liver injury, inflammation and fibrosis, and adipose tissue homeostasis were examined. RESULTS: FFC diet-fed Trail-/- mice displayed no difference in weight gain and metabolic profile when compared to WT mice on the same diet. All FFC-fed mice developed significant hepatic steatosis, which was attenuated in Trail-/- mice. TRAIL deficiency also significantly decreased FFC diet-induced liver injury as manifest by reduced serum ALT values, hepatic TUNEL-positive cells and macrophage-associated inflammation. FFC diet-associated hepatic stellate cell activation and hepatic collagen deposition were also abrogated in Trail-/- mice. In contrast to the liver, TRAIL deletion did not improve FFC diet-induced adipose tissue injury and inflammation, and actually aggravated insulin resistance. In conclusion, these observations employing genetic TRAIL inactivation suggest that NASH pathogenesis may be dissociated from other features of the metabolic syndrome and liver-targeted inhibition of TRAIL signaling may be salutary.
RESUMEN
Herein, we have identified cross-talk between the Hippo and fibroblast growth factor receptor (FGFR) oncogenic signaling pathways in cholangiocarcinoma (CCA). Yes-associated protein (YAP) nuclear localization and up-regulation of canonical target genes was observed in CCA cell lines and a patient-derived xenograft (PDX). Expression of FGFR1, -2, and -4 was identified in human CCA cell lines, driven, in part, by YAP coactivation of TBX5. In turn, FGFR signaling in a cell line with minimal basal YAP expression induced its cellular protein expression and nuclear localization. Treatment of YAP-positive CCA cell lines with BGJ398, a pan-FGFR inhibitor, resulted in a decrease in YAP activation. FGFR activation of YAP appears to be driven largely by FGF5 activation of FGFR2, as siRNA silencing of this ligand or receptor, respectively, inhibited YAP nuclear localization. BGJ398 treatment of YAP-expressing cells induced cell death due to Mcl-1 depletion. In a YAP-associated mouse model of CCA, expression of FGFR 1, 2, and 4 was also significantly increased. Accordingly, BGJ398 treatment was tumor-suppressive in this model and in a YAP-positive PDX model. These preclinical data suggest not only that the YAP and Hippo signaling pathways culminate in an Mcl-1-regulated tumor survival pathway but also that nuclear YAP expression may be a biomarker to employ in FGFR-directed therapy.
