Molecular changes associated with chronic liver damage and neoplastic lesions in a murine model of hereditary tyrosinemia type 1

• Water soaked food extended HT1 mouse survival by 3 times compared to previous studies.
• Protocol modification resulted in 100% of mice showing neoplastic lesions.
• HT1 progression is associated with a stepwise activation of stress response pathways.

Hereditary tyrosinemia type 1 (HT1) is the most severe inherited metabolic disease of the tyrosine catabolic pathway, with a progressive hepatic and renal injury and a fatal outcome if untreated. Toxic metabolites accumulating in HT1 have been shown to elicit endoplasmic reticulum (ER) stress response, and to induce chromosomal instability, cell cycle arrest and apoptosis perturbation. Although many studies have concentrated on elucidating these events, the molecular pathways responsible for development of hepatocellular carcinoma (HCC) still remain unclear. In this study the fah knockout murine model (fah−/−) was used to investigate the cellular signaling implicated in the pathogenesis of HT1. Fah−/− mice were subjected to drug therapy discontinuation (Nitisinone withdrawal), and livers were analyzed at different stages of the disease. Monitoring of mice revealed an increasing degeneration of the overall physiological conditions following drug withdrawal. Histological analysis unveiled diffuse hepatocellular damage, steatosis, oval-like cells proliferation and development of liver cell adenomas. Immunoblotting results revealed a progressive and chronic activation of stress pathways related to cell survival and proliferation, including several stress regulators such as Nrf2, eIF2α, CHOP, HO-1, and some members of the MAPK signaling cascade. Impairment of stress defensive mechanisms was also shown by microarray analysis in fah−/− mice following prolonged therapy interruption. These results suggest that a sustained activation of stress pathways in the chronic HT1 progression might play a central role in exacerbating liver degeneration.