Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease

Figure 2

Pathway linked to ER stress. Schematic representations of hepatocyte in a fatty liver. A lipid overload, free fatty acids, and cholesterol may induce ER stress leading to “unfolded protein response” in order to reestablish the ER homeostasis. Its prolonged and repetitive activation should trigger a proapoptotic and inflammatory pathway resulting in an increase of oxidative stress. The activity of UPR is fundamentally mediated through three transmembrane stress transducers (PERK, IRE1, and ATF6), which regulate the expression of proinflammatory and antioxidant genes. In a prolonged ER stress condition, the ROS production is also increased by the overexpression of ERO1, an inducible ER oxidoreductase. Saturated fatty acids and ER stress can reduce the activity or SERCA determining a disruption of ER calcium store which can act on mitochondria blocking ETC and forming mPTP resulting in an uncontrolled transition of cytochrome C and other proapoptotic factors into the cytosol. ATF4: activating transcription factor 4; ATF6: activating transcription factor 6; CHOP: C/EBP homologous protein; ER: endoplasmatic reticulum; ERO1: ER oxidoreductin 1; ETC: electron transport chain; IRE1: inositol-requiring signaling protein 1; IRS1: insulin receptor substrate 1; mPTP: mitochondrial permeability transition pore; PERK: protein kinase RNA-like ER kinase; ROS: reactive oxygen species; SERCA: sarco/endoplasmic reticulum CA²⁺-ATPase; UPR: unfolded protein response.