**2.1 Contribution of oxidative stress and mitochondrial dysfunction in NAFLD formation**

The influences of oxidative stress and mitochondrial dysfunction in NAFLD and NASH are well-recognized. Within the normal liver, β-oxidation occurs in the mitochondria but in the setting of NAFLD, this process can become overwhelmed due to elevated FFA load, leading to the generation of ROS. ROS stimulate oxidative stress with a progressive activation of mitochondrial damage and inflammatory pathways [8, 9]. Oxidative stress defines the imbalance between the production of ROS and the scavenging capacity of the antioxidant system to counteract the effect of the ROS produced. A high concentration of ROS intensifies the modifications of cellular macromolecules, such as DNA, proteins and lipids, which could lead to the deposition of damaged macromolecules and subsequently induce liver injury. Hence, the mechanism by which ROS contribute to NAFLD development may be associated with deregulated redox signaling and undifferentiating oxidative biomolecular injury (**Figure 2**) [9]. While the hepatic detoxification process in the liver serves as the main cause of oxidative stress, the biotransformation responses and physiologically generate intermediate ROS to permit the oxidation of toxins and promote their detoxification and excretion. Thus, under normal situations, the levels of ROS generated are the actual amounts needed for the normal body detoxification process and the body system syntheses many antioxidant cofactors that are essentially needed to counterbalance the generation of ROS [4, 6, 7]. On the other hand, insufficient production of endogenous antioxidant molecules and overloading of toxins may facilitate oxidative stress, which in turn may enhance tissue injury and promote the

### **Figure 2.**

*Mechanisms of endoplasmic reticulum stress induced-NAFLD. NAFLD is associated with deposition of lipids in the liver, on which lipids promote several cellular stress pathways, such as ER stress and oxidative stress. ER stress enhances UPR which is facilitated by the activation of ER proteins, including ATF6, IRE1 and PERK. Through the phosphorylation of Nrf2, which controls the transcription of antioxidant genes, PERK activation enhances the defense against oxidative stress. Additionally, PERK promotes ATF4, which in turn triggers the transcription of CHOP and controls apoptosis through the Bax protein. Apoptosis results through an interaction between activated IRE1 and TRAF2 and complex recruits Caspase-12. When ER stress is maintained by increasing FFA, PERK and ATF-6 sensors can also activate NF-kB. Additionally, hyperlipidaemia, hypercholesterolemia and obesity can raise the amount of ROS that trigger apoptosis through oxidative stress pathways. Oxidative stress and ER stress are correlated in a bidirectional manner. ATF: Activating transcription factor, CHOP: C/EBP-homologous protein, FFA: Free fatty acid, IRE1: Inositol requiring enzyme-1, NF-κB: Nuclear factor κ-light-chain-enhancer of activated B cells, Nrf2: Nuclear factor 2 erythroid 2-related factor, PERK: Protein kinase RNA-like ER kinase, ROS; reactive oxygen species, TRAF2: TNF-α receptor-associated factor 2.*

*Non-Alcoholic Fatty Liver Disease: Pathogenesis and the Significance of High-Density… DOI: http://dx.doi.org/10.5772/intechopen.108199*

inflammation process [2, 5]. Furthermore, oxidative stress has progressively shown to be one of the major essential pathological processes in the development of NAFLD and the relationship between NASH manifestation and simple steatosis. Oxidative stress has been attributed to various chronic disorders, particularly those associated with low-grade inflammation, including DM, obesity and other metabolic syndromes [2, 5]. Oxidative stress has also been investigated as the major factor associated with the pathophysiology and development of CVDs and was suggested to be a possible mechanism, that links NAFLD to CVDs. While CVDs represent the leading cause of global death and morbidity, in this respect, only a few NAFLD patients may have chronic liver disease. Another important cellular source of oxidative stress is NADPH oxidase (Nox) and its stimulation has been linked with the possible progress of liver injury. The NADPH oxidase family, such as Nox1, Nox2, and Nox4, were suggested to control the activation of hepatic apoptosis and HSCs, which are essential in the fibrogenic process [2, 4, 5].
