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

Aurèle Besse-Patin,Jennifer L Estall

doi:10.1155/2014/519153

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.

Highlights

Reactive oxygen species (ROS) are formed through radical leakage from enzymes such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [31], cyclooxygenases [32], lipoxygenases [33], and the mitochondrial ETC [34]
PGC-1α coordinates the transcriptional activity of several nuclear transcription factors such as nuclear respiratory factors 1 and 2 (NRF-1 and -2) and transactivates genes involved in the respiratory chain, mitochondrial import machinery, and transcription factors of mtDNA (such as the mtDNA transcription factor A (TFAM))
Decreased mitochondrial biogenesis associated with impaired biological activity of PGC-1α or reductions in TFAM has been observed in fatty livers [45,46,47]

Summary

Introduction

Insulin-stimulated tyrosine kinase and NADPH oxidase activation coordinate generation of an oxidized environment localized along the plasma membrane to inhibit phosphatase activity and facilitate insulin signalling. NADPH oxidase activity decreases and the local redox environment at the plasma membrane returns to a reduced state due to activity of the antioxidant systems (catalase, peroxiredoxins), restoring phosphatase activity and resetting the insulin signalling cascade at a basal state.

Results

Conclusion