Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease

Figure 3

Mechanisms of oxidative stress induced by iron metabolism derangements. The main prooxidizing mechanism is characterized by the production of hydroxyl radical from H₂O₂ and Fe²⁺ via Fenton reaction. The main source of H₂O₂ is the peroxisomal betaoxidation of very long and branched fatty acids. The hydroxyl radicals may generate lipid peroxidation of organelle membranes, leading to impairment of mitochondrial metabolism through the production on mPTP and mtDNA mutation, but also increasing the proapopotitic activity with the production of MDA. Furthermore, the chronic iron overload may also enhance the production of iNOS via NF-κB activation, leading to an increase in nitric oxide and, consequently, to a reaction with the superoxide anion, RNS. At last, the antioxidant mechanism may be inhibited by iron overload, as the activation of BACH-1, a heme-binding factor able to repress the transcription of gene encoding for HO-1, that possesses antioxidant/anti-inflammatory properties. BACH-1: BTB and CNC homology 1; MDA: malondialdehyde; mPTP: mitochondrial permeability transition pore; HO-1: hemoxygenase 1; ROS: reactive oxygen species; RNS: reactive nitrogen species; SOD1: superoxide dismutase 1.