Oxidative stress signaling underlying liver disease and hepatoprotective mechanisms

Abstract

Oxidative stress is a redox imbalance between pro-oxidants and antioxidants in favour of the former ones, leading to different responses depending on the level of pro-oxidants and the duration of the exposure. In this article, we discuss the damaging or cytoprotective signaling mechanisms associated with oxidative stress by addressing (1) the role of prolonged and severe oxidative stress and insulin resistance as determinant factors in the pathogenesis of non-alcoholic fatty liver disease associated with obesity, which, with the concurrence of nutritional factors, may determine the onset of fatty liver and its progression to steatohepatitis; and (2) the development of an acute and mild pro-oxidant state by thyroid hormone administration, which elicits the redox up-regulation of the expression of proteins affording cell protection, as a preconditioning strategy against ischemia-reperfusion liver injury.

Keywords: Insulin resistance; Liver preconditioning; Non-alcoholic fatty liver disease; Obesity; Oxidative stress; Thyroid hormone.

Figure 1

Interrelationships between the level of oxidative stress and insulin resistance, leading to hepatic steatosis and its progression to steatohepatitis, associated with overnutrition. AP-1: Activating protein 1; CYP2E1: Ethanol inducible form of cytochrome P450; FA: Fatty acids; IL-1: Interleukin-1; LCPUFA; Long-chain polyunsaturated fatty acids; NF-κB: Nuclear factor-κB; NOX2: NADPH oxidase in phagocytic cells; PPAR-α: Peroxisome proliferator-activated receptor-α; ROS: Reactive oxygen species; SREBP-1c: Sterol regulatory element binding protein-1c; TNF-α: Tumor necrosis factor-α.

Figure 2

Oxidative stress signaling in thyroid hormone (T3) liver preconditioning as mediated by redox-sensitive transcriptional factors NF-κB, AP-1, and STAT3 (A) or Nrf2 (B). AP-1: Activating protein 1; ARE: Antioxidant responsive element; GdCl3: Gadolinium chloride; IL: Interleukin; iNOS: Inducible nitric oxide synthase; MnSOD: Manganese superoxide dismutase; NF-κB: Nuclear factor-κB; Nrf2: Nuclear factor-erythroid 2-related factor 2; QO2: Rate of oxygen consumption; TNF-α: Tumor necrosis factor-α; STAT3: Signal transducer and activator of transcription 3; TR: Thyroid hormone receptor; UCP: Uncoupling protein.