A novel brick on the wall of non-alcoholic fatty liver disease (NAFLD): Nuclear receptor coactivator 4 (NCOA4)

Dysmetabolic iron overload syndrome (DIOS) defines a moderate increase in body iron load in the absence of an identifiable cause of iron excess, and one of its main target organs is the liver. DIOS has been reported to be associated with hyperferritinemia, non-alcoholic fatty liver disease (NAFLD), hyperlipidemia, and atherosclerotic heart disease. Despite iron overload, hepcidin overexpression has been reported in patients with DIOS. However, underlying mechanisms for impaired hepcidin function have not been illuminated yet. Nuclear receptor coactivator 4 (NCOA4) plays a significant role in intracellular iron traffic by regulating cellular iron levels as being the rate-limiting factor for ferritinophagy. Functional studies on NCOA4 have revealed that loss of NCOA4 function causes ferritin accumulation in every tissue examined. Here, we hypothesized that some of the patients with NAFLD develop DIOS, because of dysmetabolic overexpression of hepcidin that inhibits NCOA4 expression, leading to ferritin accumulation within hepatocytes, but not reticuloendothelial cells of the liver.