Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease

Figure 1

Mechanisms of mitochondrial dysfunction involved in the production of oxidative stress. An increase of mitochondrial betaoxidation activity, due to a lipid overload, may induce an impairment of electron transport chain, resulting in an “electron leakage.” The reaction between oxygen and protons catalyzed by cytochrome C oxidase (VI complex) is impaired, and electrons may interact directly with oxygen forming ROS. Furthermore, the generation of mitochondrial membrane potential is reduced following the reduction of proton extrusion from the matrix, weakening the activity of ATP synthase. ROS production may exacerbate the mitochondrial dysfunction due to electron leakage following the generation of mtDNA mutation and highly reactive aldehydes (MDA, 4-HNE) produced through lipid peroxidation. Mitochondrial CYP2E1 is a direct source of ROS. A reduction of antioxidant mechanism as GPx and MnSOD was also observed in the NASH model. At last, the incomplete suboptimal oxidation of acyl-carnitine leads to accumulation of lipotoxic intermediates (Cer, DAGs), which can act as an inflammatory intermediate altering the insulin signaling. 4-HNE: 4-hydroxy-2-nonenal; Cer: ceramides; CYP2E1: cytochrome P450 2E1; DAGs: diacylglycerols; FFAs: free fatty acids; GPx: glutathione peroxidase; GSH: glutathione; MDA: malondialdehyde; MnSOD: manganese superoxide dismutase; ROS: reactive oxygen species.