An Intimate Relationship between ROS and Insulin Signalling: Implications for Antioxidant Treatment of Fatty Liver Disease

Abstract

Oxidative stress damages multiple cellular components including DNA, lipids, and proteins and has been linked to pathological alterations in nonalcoholic fatty liver disease (NAFLD). Reactive oxygen species (ROS) emission, resulting from nutrient overload and mitochondrial dysfunction, is thought to be a principal mediator in NAFLD progression, particularly toward the development of hepatic insulin resistance. In the context of insulin signalling, ROS has a dual role, as both a facilitator and inhibitor of the insulin signalling cascade. ROS mediate these effects through redox modifications of cysteine residues affecting phosphatase enzyme activity, stress-sensitive kinases, and metabolic sensors. This review highlights the intricate relationship between redox-sensitive proteins and insulin signalling in the context of fatty liver disease, and to a larger extent, the importance of reactive oxygen species as primary signalling molecules in metabolically active cells.

Figure 1

Molecular mechanisms linking ROS, antioxidants, and the insulin signalling pathway. To allow a response to insulin stimulation, ROS are relieving insulin receptor's inhibition by phosphatases such as PTP1B. When the cellular environment shifts to an oxidative one, because of increased mitochondrial respiration and ROS release for example, the stress-sensitive kinases are activated upon redox-sensitive phosphatases inhibition. Theses kinases are inhibiting signal amplification by inhibitory phosphorylation of IRS proteins. Mitochondrial ROS can be regulated by PGC-1α-dependent detoxification system (Sirt3, SOD, GPx) or by specific mitochondrial antioxidants (SS31, MitoQ).