Review Article

Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease

Table 1

Overview of the major pathophysiological mechanisms involved in oxidative stress in NAFLD addressed within the present paper, with the corresponding references.

Pathophysiological mechanisms of oxidative stressMechanism (with references)
Increasing prooxidantDecreasing antioxidant

Mitochondrial dysfunctionImpairment of oxidative capacity of ETC, resulting in an “electron leakage” [21]GSH depletion with reduction of GPx activity [41]
Accumulation of Cer and DAGs due to incomplete betaoxidation of acyl-carnitine [34]Reduced activity of MnSOD, polymorphism C47T of SOD2 gene [42]
mtDNA mutation [25]Impaired activity of cytochrome C [35]
Production of reactive aldehydes (MDA, 4-HNE) through lipid peroxidation [43]
Increase activity of CYP2E1, polymorphism of C2 allele [3740]

ER stressProlonged activation of UPR leading to
(i) overexpression of ERO1 [49]
(ii) calcium disruption due to reduced activity or SERCA [55]
(iii) upregulation of CHOP mediated by activation of PERK and ATF6 [50]
Prolonged activation of UPR leading to
(i) inhibition of Nrf2 by PERK resulting in the depletion of GSH [59]

Iron metabolism derangementsDisruption of peroxisomal membrane [66]GSH depletion—decreased GPx efficiency [67]
Enhanced iNOS expression via NF-κB activation [67]Inhibition of HO-1 by activation of BACH-1 [7074]
Production of reactive aldehydes (MDA) through lipid peroxidation [64]Iron actin as a direct competitive antagonist of antioxidant enzymes [69]

Inappropriate inflammatory response mediated by GUT-liver axisUpregulation of proinflammatory pathways and NADPH oxidase system due to bacterial and bacterial product translocation [80, 81]Lack of inhibition of inflammatory response by NPRL-3 and -6 [85, 86]
Activation of inflammasomes resulting in cleavage of cytokines precursors (pro-IL1β, pro-IL18) [82]
Endogenous alcoholic production by alcohol-producing bacteria [89]

Insulin resistance and endothelial dysfunctionUpregulation of Ras/MAPK pathway involved in cell proliferation [94]Decrease of eNOS activation due to IR [94]
Enhanced iNOS activity due to increase expression of proinflammatory cytokines in IR [96]

4-HNE: 4-hydroxy-2-nonenal; ATF6: activating transcription factor 6; BACH-1: BTB and CNC homology 1; Cer: ceramides; CHOP: C/EBP homologous protein; CYP2E1: cytochrome P 450 2E1; DAGs: diacylglycerols; ER: endoplasmatic reticulum; ERO1: ER oxidoreductin 1; ETC: electron transport chain; GPx: glutathione peroxidase; GSH: glutathione; HO-1: hemoxygenase 1; IR: insulin resistance; MDA: malondialdehyde; MnSOD: manganese superoxide dismutase; NPRL: NOD-like receptor protein; Nrf2: nuclear factor- (erythroid-derived 2-) like 2; PERK: protein kinase RNA-like ER kinase; SERCA: sarco/endoplasmic reticulum CA2+-ATPase; UPR: unfolded protein response.