Hormetic responses of thyroid hormone calorigenesis in the liver: Association with oxidative stress.
Thyroid hormone (L-3,3',5-triiodothyronine, T(3)) exerts calorigenic effects by accelerating mitochondrial O(2) consumption through transcriptional activation of respiratory genes, with consequent increased reactive oxygen species (ROS) production. In the liver, ROS generation occurs at different sites of hepatocytes and in the respiratory burst of Kupffer cells, triggering the activation of the transcription factors nuclear factor-kappaB, signal transducer and activator of transcription 3, and activating protein 1. Under these conditions, the redox upregulation of Kupffer cell-dependent expression of cytokines [tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6] is achieved, which upon interaction with specific receptors in hepatocytes trigger the expression of antioxidant enzymes (manganese superoxide dismutase, inducible nitric oxide synthase), antiapoptotic proteins (Bcl-2), and acute-phase proteins (haptoglobin, beta-fibrinogen). These responses and the promotion of hepatocyte and Kupffer cell proliferation observed represent hormetic effects re-establishing redox homeostasis, promoting cell survival, and protecting the liver against ischemia-reperfusion (IR) injury. It is proposed that hormesis underlying T(3) action may constitute a novel preconditioning strategy for IR injury during liver surgery in man or in liver transplantation using reduced-size grafts from living donors, considering that (i) with the exception of the controversial ischemic preconditioning, all other studied strategies have failed to reach the clinical setting and (ii) T(3) is a well-tolerated therapeutic agent that either lacks major adverse effects or has minimal and controlled side effects.
Videla
Luis A
LA
Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile. lvidela@med.uchile.cl
D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D013963:Thyroid Hormones / Q000378:metabolism* / Q000494:pharmacology
D013963:Thyroid Hormones