Hormetic responses of thyroid hormone calorigenesis in the liver: Association with oxidative stress

Abstract

SummaryThyroid hormone (L-3,3 0 ,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-jB, 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-a, 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, b-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. IUBMBIUBMB Life, 62(6): [460][461][462][463][464][465][466] 2010

Recent advances in liver preconditioning: Thyroid hormone, n-3 long-chain polyunsaturated fatty acids and iron

“…T�, n-3 LCPUFA and iron can be considered as hormetic agents [91,92] , which are defined as compounds inducing a dose-response phenomenon characterized by biologically beneficial effects in the low-concentration (dose) range (organ preconditioning) [26][27][28] and harmful responses at high concentrations (doses) or after prolonged exposure (thyrotoxicosis [9�] , gastrointestinal upset/increase bleeding time [48] and hemochromatosis [94] , respectively). Organ preconditioning by these hormetic agents is not restricted to the liver [26][27][28] , considering that (1) thyroid 1) thyroid ) thyroid hormone-induced preconditioning against IR injury is also observed in the heart [95,96] , with a pattern of protection comparable to that of ischemic preconditioning [97] ; (�) beneficial effects of n-3 LCPUFA have been dem-�) beneficial effects of n-3 LCPUFA have been dem-) beneficial effects of n-3 LCPUFA have been demonstrated in rheumatoid arthritis, inflammatory bowel disease, coronary artery disease, asthma and sepsis, conditions with inflammation as a key component of their pathology [48] , in addition to neuroinflammation in all major central nervous system diseases [98] ; and (�) protec-�) protec-) protective effects of iron are reported in cardiomyocytes and heart [99][100][101] , oligodendroglia cells [102] and neurones [10�] .…”

Liver preconditioning induced by iron in a rat model of ischemia/reperfusion

“…Although the last three preconditioning strategies have clinical potential, liver preconditioning by thyroid hormone or n-3 long-chain polyunsaturated fatty acids have not been evaluated in man, whereas ischemic preconditioning in human liver resections or in human liver transplantation remains controversial (Videla, 2010). The data presented in this work indicate that Fe administration to rats constitutes an alternate preconditioning strategy that may be of relevance to clinical application, taking into account that repeated injections of 100-125 mg/kg of iron complexes by intramuscular or intravenous routes (100-125 mg/kg, 1-3 times/week for 4-12 weeks) are considered as valid and well tolerated therapeutic strategies in human anemia treatments (Silverstein and Rodgers, 2004;Bayraktar and Bayraktar, 2010).…”

Thyroid hormone induction of mitochondrial activity is coupled to mitophagy via ROS-AMPK-ULK1 signaling

“…Indeed, previous reports have shown that severe hyperthyroidism is associated with increased ROS production and cellular damage. [21][22][23][24][25] Surprisingly, although T 3 has been reported to concurrently induce mitochondrial activity and turnover, 26 the underlying mechanism for their interrelationship is not well understood.…”