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

Figure 2

The effect of oxidative stress (OS) in hepatic tissue during nonalcoholic fatty liver disease (NAFLD). In NAFLD, significant lipidic increase inside the liver results in lipotoxicity, which induces oxidative stress (OS), with a marked reactive oxygen species (ROS) increase. OS is the main contributor to NAFLD development due to decreased antioxidant systems, mitochondrial dysfunction, and an increase in unfolded protein response (UPR) by endoplasmic reticulum (ER) stress. Furthermore, an OS increment is due to NAFLD’s negative consequences as the iron increase and hypoxia. Lipotoxicity given by NAFLD can directly induce OS and induce organelle damage, as mitochondrial and ER dysfunction. Also, there is an impairment in β-oxidation due to a decrease in peroxisome proliferator-activated receptor alpha (PPARα) activity, which increases intrahepatic lipids levels, inducing hepatic inflammation. At the same time, the phospholipid oxidation in the mitochondrial membrane decreases electron transport chain (ETC) that increases electron leakage, diminishing adenosine triphosphate (ATP) production, and generating antioxidant systems dysfunction characterized by the decrease in nuclear factor-(erythroid-derived 2) (Nrf2) activity. Together, these mechanisms related to mitochondrial dysfunction increases OS. On the other hand, lipotoxicity induces an increase of UPR, causing ER dysfunction. The ER dysfunction increases Sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) activity and intracellular Ca⁺² (Ca⁺²i) levels, leading to the opening of the mitochondrial permeability transition pore (mPTP), causing an increase in ROS production. The ROS increment causes a decrease in nitric oxide (NO) levels, causing a reduction in the liver’s vasodilatation. Together, all these mechanisms increase ROS production, increasing OS in hepatic tissue, which causes inflammation, hepatocytes apoptosis, and fibrosis during NAFLD progression. Created with http://BioRender.com