Thrombospondin-1 Exacerbates Acute Liver Failure and Hepatic Encephalopathy Pathology in Mice by Activating Transforming Growth Factor β1

Severe hepatic insults can lead to acute liver failure and hepatic encephalopathy (HE). Transforming growth factor beta 1 (TGF beta 1) has been shown to contribute to HE during acute liver failure; however, TGF beta 1 must be activated to bind its receptor and generate downstream effects. One protein that can activate TGF beta 1 is thrombospondin-1 (TSP-1). Therefore, the aim of this study was to assess TSP-1 during acute liver failure and HE pathogenesis. C57Bl/6 or TSP-1 knockout (TSP-1(-/-)) mice were injected with azoxymethane (AOM) to induce acute liver failure and HE. Liver damage, neurologic decline, and molecular analyses of TSP-1 and TGF beta 1 signaling were performed. AOM-treated mice had increased TSP-1 and TGF beta 1 mRNA and protein expression in the liver. TSP-1(-/-) mice administered AOM had reduced liver injury as assessed by histology and serum transaminase levels compared with C57Bl/6 AOM-treated mice. TSP-1(-/-) mice treated with AOM had reduced TGF beta 1 signaling that was associated with less hepatic cell death as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and cleaved caspase 3 expression. TSP-1(-/-) AOM-treated mice had a reduced rate of neurologic decline, less cerebral edema, and a decrease in microglia activation in comparison with C57Bl/6 mice treated with AOM. Taken together, TSP-1 is an activator of TGF beta 1 signaling during AOM-induced acute liver failure and contributes to both liver pathology and HE progression.