Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities.
Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease in the world. It encompasses a histological spectrum, ranging from simple, nonprogressive steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis and hepatocellular carcinoma. While liver-related complications are confined to NASH, emerging evidence suggests both simple steatosis and NASH predispose to type 2 diabetes and cardiovascular disease. The pathogenesis of NAFLD is currently unknown, but accumulating data suggest that oxidative stress and altered redox balance play a crucial role in the pathogenesis of steatosis, steatohepatitis, and fibrosis. We will examine intracellular mechanisms, including mitochondrial dysfunction and impaired oxidative free fatty acid metabolism, leading to reactive oxygen species generation; additionally, the potential pathogenetic role of extracellular sources of reactive oxygen species in NAFLD, including increased myeloperoxidase activity and oxidized low density lipoprotein accumulation, will be reviewed. We will discuss how these mechanisms converge to determine the whole pathophysiological spectrum of NAFLD, including hepatocyte triglyceride accumulation, hepatocyte apoptosis, hepatic inflammation, hepatic stellate cell activation, and fibrogenesis. Finally, available animal and human data on treatment opportunities with older and newer antioxidant will be presented.
Department of Internal Medicine, University of Turin, Turin, Italy.
Roberto
R
Gambino
Giovanni
G
Musso
Maurizio
M
Cassader
D054392:Adipokines / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D009195:Peroxidase / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity
D054392:Adipokines; D000975:Antioxidants; D005230:Fatty Acids, Nonesterified; D008077:Lipoproteins, LDL; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D009195:Peroxidase