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.

Keywords: ER stress; ROS; antioxidant compounds; antioxidant response; lipid metabolism; lipotoxicity; mitochondrial dysfunction; non-alcoholic liver disease; oxidative stress.

Figure 1

Overview of oxidative stress and antioxidants in the context of non-alcoholic fatty liver disease (NAFLD). The pathogenesis of NAFLD is a multifactorial process involving several mechanisms, ultimately leading to a disturbed redox balance. Impairment of lipid metabolism, e.g., by excessive dietary intake of fat and carbohydrates, leads to steatosis. This can be aggravated by insulin resistance. Free fatty acids (imported by, e.g., CD36 or FAT) such as palmitate cause lipotoxicity by increasing the levels of toxic lipid species such as ceramides and diacylglycerols (DAG). Mitochondrial dysfunction, impairment of β-oxidation, and endoplasmic reticulum (ER) stress can all increase the generation of ROS leading to lipid peroxidation. ER stress induces the UPR, i.e., Unfolded Protein Response. Sustained ER stress and sustained activation of the UPR will trigger activation of the ER stress proteins PERK, ATF6, ATF4, and CHOP, leading to a proinflammatory response and activation of cell death pathways in hepatocytes. ER stress might lead to the activation of sterol regulatory element-binding protein 1C (SREBP1c) and further translocation to the nucleus, thus promoting hepatic lipogenesis. The impaired redox balance also affects the antioxidant response (e.g., the Nrf2 pathway) and leads to decreased levels of antioxidants (e.g., GSH and SOD).

Figure 2

Potential therapeutic strategies for NAFLD based on antioxidant potential. Main mechanisms related to the potential therapeutic effect of antioxidant agents in NAFLD, according to experimental evidence. During NAFLD progression, ROS overproduction leads to an impairment of the antioxidant balance and lipid metabolism and to a proinflammatory response, resulting in liver injury. Therapeutic antioxidant effects are mediated by the activation of Antioxidant Response Elements (AREs) regulated by the Nrf2 and NF-kB pathways. Restoration of mitochondrial function normalizes lipid metabolism by restoring the balance between lipolysis and triglyceride synthesis and improves β-oxidation and ATP generation. Finally, anti-inflammatory effects, mainly via inhibition of NF-κB-dependent transcription, prevent liver injury and non-alcoholic steatohepatitis (NASH) progression.