NADPH Oxidases Connecting Fatty Liver Disease, Insulin Resistance and Type 2 Diabetes: Current Knowledge and Therapeutic Outlook

Abstract

Nonalcoholic fatty liver disease (NAFLD), characterized by ectopic fat accumulation in hepatocytes, is closely linked to insulin resistance and is the most frequent complication of type 2 diabetes mellitus (T2DM). One of the features connecting NAFLD, insulin resistance and T2DM is cellular oxidative stress. Oxidative stress refers to a redox imbalance due to an inequity between the capacity of production and the elimination of reactive oxygen species (ROS). One of the major cellular ROS sources is NADPH oxidase enzymes (NOX-es). In physiological conditions, NOX-es produce ROS purposefully in a timely and spatially regulated manner and are crucial regulators of various cellular events linked to metabolism, receptor signal transmission, proliferation and apoptosis. In contrast, dysregulated NOX-derived ROS production is related to the onset of diverse pathologies. This review provides a synopsis of current knowledge concerning NOX enzymes as connective elements between NAFLD, insulin resistance and T2DM and weighs their potential relevance as pharmacological targets to alleviate fatty liver disease.

Keywords: NADPH oxidase; NAFLD; NOX; ROS; diabetes; hepatosteatosis; insulin resistance; nonalcoholic fatty liver disease; oxidative stress; reactive oxygen species.

Figure 1

Cellular redox homeostasis. The main sources of cellular superoxide (O₂⁻) are mitochondria and NADPH oxidase (NOX) enzymes. Hydrogen peroxide (H₂O₂) is produced by the peroxisome NOX4 and the two dual oxidase (DUOX) enzymes. O₂⁻ is transformed by superoxide dismutase (SOD) into H₂O_2. H₂O₂ elimination can occur through different enzyme systems that allow for the conversion of H₂O₂ into H₂O. In addition, H₂O₂ can give rise to a highly toxic hydroxyl radical (OH) in a metal-catalyzed reaction. NADPH is replenished from different cellular metabolic sources. GPX: glutathione peroxidase; GSH: Reduced form of glutathione; GSSG: glutathione disulfide, oxidized form of glutathione; GR: glutathione reductase; NADPH: Nicotinamide adenine dinucleotide phosphate; Prx: Peroxiredoxin proteins; Trx-red: Reduced form of thioredoxin; Trx-ox: Oxidized form of thioredoxin; TrxR: thioredoxin reductase.