Activation of Endoplasmic Reticulum-Specific Stress Responses Associated with the Liver Disorder Hereditary Haemochromatosis

Category: Hepatology Aims: The aim of this study was to characterise the intracellular events involved in the molecular pathogenesis of HH induced liver disease, in particular the unfolded protein response (UPR) indicated by increased GRP78/BiP and GRP94 protein production. Methods: Liver biopsies were obtained from normal and haemochromatotic (C282Y +/+) subjects. ER stress signals were assessed including apoptosis signals to include caspase-4 and caspase-9 activity, along with cytochrome c release. Results: Comparing haemochromatotic biopsies to normal liver samples we found UPR activation by increased expression of GRP78/BiP and GRP94 protein production. We also found ER stress-induced apoptosis in the form of caspase-4, caspase-9 activation along with cytochrome c release. This study is the first report of the molecular stress mechanisms associated with HH, indicating that activation of the UPR is enhanced in patients with HH. We demonstrated activation of the UPR in the form of increased GRP78/BiP and GRP94 protein production in haemochromatotic biopsies compared to normal liver samples. We also demonstrated specific apoptosis pathway whereby cytochrome c release is induced; caspase-4 localized in the ER becomes activated along with caspase-9. Conclusions: These finding further elucidate the molecular events in the evolution of liver disease in patients with HH.