title: Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis.
abstract: The worldwide rising prevalence of obesity and insulin resistance is associated with a parallel increase in nonalcoholic fatty liver disease (NAFLD). NAFLD is characterized by excess accumulation of triglyceride in the hepatocyte due to increased inflow of free fatty acids and/or de novo lipogenesis caused by various drugs and multiple defects in energy metabolism. Accumulation of lipids in the hepatocyte impairs the oxidative capacity of the mitochondria, increasing the reduced state of the electron transport chain (ETC) complexes and stimulating peroxisomal and microsomal pathways of fat oxidation. The consequent increased generation of reactive oxygen species (ROS) and reactive aldehydic derivatives causes oxidative stress and cell death, via ATP, NAD, and glutathione depletion and DNA, lipid, and protein damage. Oxidative stress also triggers production of inflammatory cytokines, causing inflammation and a fibrogenic response. This ultimately results in the development of nonalcoholic steatohepatitis (NASH), which can result in end-stage liver disease. The current therapeutic strategies for NASH treatment are mostly directed toward correction of the risk factors. Stimulation of mitochondrial function may also prevent NASH development, protecting the cell against the increased flux of reduced substrates to the ETC and ROS generation.
authors: Center for Neuroscience and Cell Biology, Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal.
authors: Anabela P
authors: AP
authors: Rolo
authors: João S
authors: JS
authors: Teodoro
authors: Carlos M
authors: CM
authors: Palmeira
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004249:DNA Damage; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005234:Fatty Liver / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007333:Insulin Resistance; D015227:Lipid Peroxidation; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D059748:Proteolysis; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014280:Triglycerides / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D005230:Fatty Acids, Nonesterified; D017382:Reactive Oxygen Species; D014280:Triglycerides