Tauroursodeoxycholic acid: Relieving the pathogenesis of HFE C282Y hereditary hemochromatosis
Authors: Matthew W. Lawless, Arun K. Mankan, Anthony W. Ryan, Suzanne Norris
Journal: Hepatology (2008)

We read with interest the article by Pietrangelo, which correctly points out the recent advancement in the field of hemochromatosis and highlights analogies with diabetes.1 The homozygous C282Y mutation of the hemochromatosis protein HFE (the most common form of iron overload disease) induces the formation of protein aggregates that are retained in the endoplasmic reticulum (ER). Recent studies2, 3 demonstrate HFE C282Y protein aggregates in vivo and in vitro in the ER, associated with the activation of oxidative stress, and thereby advocate the contribution of iron-induced oxidative stress toxicity in the pathogenesis of this disease.2, 3 Pietrangelo importantly suggests that recognizing the analogies between HFE C282Y hemochromatosis and a classic endocrine disease such as diabetes simplifies the matter and places HFE C282Y hemochromatosis within its natural pathogenic context. Indeed, accumulating evidence suggests that protein folding and generation of reactive oxygen species (ROS) as a by-product of protein oxidation in the ER are closely linked events. Furthermore, persistent oxidative stress and protein aggregates are now known to play predominant roles in the pathogenesis of diabetes.4 Recent studies demonstrating that the HFE C282Y protein itself also forms aggregates suggests another important similarity with diabetes. Thus, recognition of HFE C282Y hereditary hemochromatosis (HH) aberrant protein aggregation is an important consideration for new and more effective approaches to diagnosis and treatment. A close relationship exists between oxidative stress and ER stress activation in various pathological conditions such as cardiovascular disease, cancer, neurological disorders, and diabetes. The ER is connected with ROS generation and changes in redox state, and the presence of ROS affects Ca2+ homeostasis by modulating the functionality of ER-based channels and buffering chaperones. Importantly, these recent studies propose tauroursodeoxycholic acid (TUDCA), a nontoxic antioxidant compound approved by the US Food and Drug Administration that is effective in preventing oxidative stress-induced cytotoxic processes, as a potentially important therapeutic for HFE C282Y HH iron overload–induced oxidative stress. Treatment with TUDCA impedes the activation of oxidative stress–induced toxicity associated with HFE C282Y mutant protein aggregates. TUDCA has been used successfully as a treatment to directly reduce cell damage and improve affected signaling pathways in cell necrosis-apoptosis or organ fibrosis in ER stress–induced pathogenesis brought on by protein aggregation, particularly in a mouse model of type 2 diabetes.5, 6 Moreover, during excess iron overload and resultant oxidative stress, in addition to iron chelation, TUDCA may prove beneficial to relieve aberrant oxidative stress and pathogenesis in patients with the HFE C282Y mutation. The recognition of the similarity between diabetes and HFE C282Y hemochromatosis in the context of ER stress suggests intriguing possibilities for new and more effective approaches to diagnosis and treatment. Furthermore, treatment with TUDCA may offer an additional therapy for HH management. Matthew W. Lawless*, Arun K. Mankan*, Anthony W. Ryan*, Suzanne Norris*, * Hepatology Research Division and Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, St. James Hospital, Dublin, Ireland.