Oxidation-Specific Epitopes in Non-Alcoholic Fatty Liver Disease

Abstract

An improper balance between the production and elimination of intracellular reactive oxygen species causes increased oxidative stress. Consequently, DNA, RNA, proteins, and lipids are irreversibly damaged, leading to molecular modifications that disrupt normal function. In particular, the peroxidation of lipids in membranes or lipoproteins alters lipid function and promotes formation of neo-epitopes, such as oxidation-specific epitopes (OSEs), which are found to be present on (lipo)proteins, dying cells, and extracellular vesicles. Accumulation of OSEs and recognition of OSEs by designated pattern recognition receptors on immune cells or soluble effectors can contribute to the development of chronic inflammatory diseases. In line, recent studies highlight the involvement of modified lipids and OSEs in different stages of the spectrum of non-alcoholic fatty liver disease (NAFLD), including inflammatory non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. Targeting lipid peroxidation products shows high potential in the search for novel, better therapeutic strategies for NASH.

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

“…Indeed, lipid peroxidation, which is a common feature of NAFLD and NASH [ 11 ], generates oxidized phospholipids, such as phosphocholine on oxidized phospholipids and oxidized cardiolipin, and reactive aldehydes, among which the most studied and best characterized are malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Interestingly, both of these oxidative stress-derived molecules act as direct inducers of hepatic inflammation [ 12 ] and as antigenic adducts named oxidative stress-derived epitopes or oxidation-specific epitopes (OSEs), by reacting with self-cellular macromolecules [ 13 ]. Indeed, oxidative stress molecules released from damaged parenchymal and non-parenchymal liver cells act as damage-associated molecular patterns (DAMPs) by interacting with membrane receptors, such as the Toll-like (TLRs) and other receptors expressed on immune system cells, with the final aim of alerting the host and promote their removal [ 14 ], thereby activating innate immunity responses [ 15 ].…”

“…Therefore, the peroxidation of lipids, besides altering their physiological functions, promotes the formation of these macromolecular neo-epitopes, named OSEs, whose presence has been observed in lipoproteins, dying cells, and extracellular vesicles. Increased presence of OSEs generated by MDA, 4-HNE, and oxidized phospholipids has been extensively demonstrated in the diseased liver (see [ 13 ] for an exhaustive review), and a correlation between their abundance and the severity of NAFLD and NASH has been demonstrated by both experimental [ 12 ] and clinical studies [ 17 ]. Coherently, targeting oxidized phospholipids has been suggested as a therapeutic strategy for the management of hepatic inflammation [ 18 ] and, more recently, for NASH [ 19 ].…”

Role of CD4+ T-cells in the pathology of non-alcoholic fatty liver disease and related diseases

“…It is well known that oxidative stress is involved in the pathophysiology of NAFLD by promoting hepatocellular death, inflammation, fibrosis, and carcinogenesis [75] . The highly reactive aldehydes generated during lipid peroxidation modify self-molecules and form antigenic adducts, known as oxidation specific epitopes (OSEs) [76,77] . Therefore, hepatocyte oxidative stress may be an important trigger for both humoral and cellular immune responses in the liver by forming OSEs [21,22,77] .…”

TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species

“…The initial step in generation of ROS involves the formation of superoxide from molecular oxygen (O 2 ). The chronic diseases or acute injuries listed above provide intracellular conditions favourable for increased activity of the reactions that generate superoxide and/or a rapid increase in O 2 , such as what occurs in ischemia–reperfusion [ 1 , 3 , 4 , 8 , 10 ]. H 2 O 2 , which is formed in vivo from superoxide ( Figure 1 ), is reasonably stable in solution in the laboratory, and has been widely used experimentally as a source of ROS in in vitro studies of liver oxidative stress employing liver cells in culture.…”

“…Many acute and chronic liver diseases are recognised. For almost all of these, oxidative stress and reactive oxygen species (ROS) play a significant role in the initiation and progression of the disease [1,[3][4][5][6][7][8][9]. Those liver diseases, or liver injuries, especially important when considering the role of oxidative stress, are acute liver injury caused by drug toxicity or ischemia-reperfusion injury, and the chronic liver diseases hepatitis B and C, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).…”