Role of Oxidative Stress in Hepatic and Extrahepatic Dysfunctions during Nonalcoholic Fatty Liver Disease (NAFLD)

Figure 4

Harmful effects of oxidative stress (OS) in extrahepatic tissues due to nonalcoholic fatty liver disease (NAFLD). In skeletal muscle, NAFLD is responsible for the development of sarcopenia and fibrosis. NAFLD causes an increase of proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6)), reactive oxygen species (ROS) production, classical renin-angiotensin system (RAS) activation, and hyperammonemia (HA), which stimulates an increment in myostatin levels. Together these factors are responsible for increased NADPH oxidase (NOX) activity and mitochondrial dysfunction, which produce ROS. Furthermore, ROS’s increment increases the ubiquitin-proteasome system (UPS) and autophagy activity, favoring sarcopenia. Simultaneously, the increase in ROS stimulates higher production of collagen III and fibronectin, contributing to fibrosis in skeletal muscle. Concerning the cardiovascular system, the ROS increment by NAFLD causes impairment in cardiac and vascular functions. ROS is responsible for impaired ion flux, causing impaired contractility, ventricle hypertrophy, and cardiomyocytes apoptosis. ROS and the RAS activity at the vascular level cause portal hypertension and endothelial dysfunction (ED), characterized by endothelial inflammation and lipotoxicity in the tissue. The renal system suffers alterations in excretion due to glomerular and tubular damage by NAFLD. All these damages are caused mainly by vasoconstriction due to NAFLD, which causes hypoxia, inflammation, increasing NOX, xanthine oxidase (XO) activity, and reducing nuclear factor-(erythroid-derived 2) (Nrf2) levels, raising even more ROS levels. At the central nervous system, NAFLD causes hyperammonemia (HA), which provoked astrocyte swelling. Astrocyte swelling increases NOX and nNOS activity, causing an increase in ROS levels. The increment in ROS levels triggers protein tyrosine nitration, ribonucleic acid (RNA) oxidation, and Zn⁺² mobilization. On the other hand, NAFLD increases ROS levels in the bloodstream; this ROS causes progressive demyelination of peripheral nerves with eventual axonal loss. Created with http://BioRender.com