Massive hepatic apoptosis associated with TGF-beta1 activation after Fas ligand treatment of IGF binding protein-1-deficient mice.

Acute liver failure caused by viral hepatitis or toxic damage involves both apoptotic and necrotic pathways. IGF binding protein-1 (IGFBP-1), a hepatocyte-derived secreted protein, is required for normal liver regeneration. To determine whether IGFBP-1 could prevent liver injury that entails direct stimulation of hepatocyte apoptosis, IGFBP-1(-/-) mice, IGFBP-1(+/+) mice, and mice pretreated with Ab's against IGFBP-1 were treated with a normally sublethal dose of Fas agonist. IGFBP-1 deficiency was associated with massive hepatocyte apoptosis and caspase activation within 3 hours of Fas agonist treatment, which could be corrected by pretreatment with IGFBP-1. IGFBP-1-deficient livers had enhanced signaling via the integrin receptor at early times (0.5 to 1 hour) after Fas agonist treatment accompanied by elevated activated matrix metalloproteinase-9 (MMP-9), a known target of fibronectin signaling and activator of TGF-beta. Within 3 hours of Fas agonist treatment, elevated expression of active TGF-beta1, a hepatocyte apoptogen, was observed in IGFBP-1-deficient livers that correlated with the appearance of the apoptotic process. Both MMP-9 and TGF-beta1 expression were suppressed by IGFBP-1 treatment, supporting their role in the apoptotic process. IGFBP-1(-/-) mice also displayed increased injury in a toxic hepatic injury model caused by CCl(4). These findings indicate that IGFBP-1 functions as a critical hepatic survival factor in the liver by reducing the level of proapoptotic signals.