Role of Oxidative Stress in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: Implications for Prevention and Therapy

Abstract

Oxidative stress (OxS) is considered a major factor in the pathophysiology of inflammatory chronic liver diseases, including non-alcoholic liver disease (NAFLD). Chronic impairment of lipid metabolism is closely related to alterations of the oxidant/antioxidant balance, which affect metabolism-related organelles, leading to cellular lipotoxicity, lipid peroxidation, chronic endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Increased OxS also triggers hepatocytes stress pathways, leading to inflammation and fibrogenesis, contributing to the progression of non-alcoholic steatohepatitis (NASH). The antioxidant response, regulated by the Nrf2/ARE pathway, is a key component in this process and counteracts oxidative stress-induced damage, contributing to the restoration of normal lipid metabolism. Therefore, modulation of the antioxidant response emerges as an interesting target to prevent NAFLD development and progression. This review highlights the link between disturbed lipid metabolism and oxidative stress in the context of NAFLD. In addition, emerging potential therapies based on antioxidant effects and their likely molecular targets are discussed.

Pirfenidone modifies hepatic miRNAs expression in a model of MAFLD/NASH

“…Furthermore, ROS cause lipid peroxidation and cytokine production, which contributes to hepatocellular injury and fibrosis, promoting the progression from simple steatosis to nonalcoholic steatohepatitis 68 . Oxidative stress in MAFLD induces hepatic stellate cell activation, the most important producer of extracellular matrix 77 , 78 . In summary, increased expression of miR-21a-5p, miR-34a-5p, miR-122-5p and miR-103-3p in this MAFLD/NASH model was reversed with prolonged-release pirfenidone.…”

The Role of Oxidative Stress in NAFLD–NASH–HCC Transition—Focus on NADPH Oxidases

“…As hinted in the Introduction, the role of oxidative stress in liver diseases associated with metabolic imbalances, such as NAFLD and NASH, is well established, and numerous studies with precise mechanistic purposes have been recently published (see [ 9 ] for a recent review). However, the complex interplay between oxidative stress mediators and the mechanisms causing and sustaining liver dysfunction is still far to be completely understood.…”

Mitochondrial Mutations and Genetic Factors Determining NAFLD Risk

“…Such mitochondria produce less ATPs and more ROS, and due to the incomplete FAO, also release toxic lipid intermediates that can cause further liver injury [ 22 , 23 ]. Simultaneously, the antioxidant biosynthesis system is not sufficient to neutralize surplus ROS; thus, OS also contributes to the hepatocytes’ stress pathways, inflammation, fibrogenesis, and further NAFLD progression to NASH [ 24 ].…”