Metabolic Basis for Thyroid Hormone Liver Preconditioning: Upregulation of AMP-Activated Protein Kinase Signaling

Abstract

The liver is a major organ responsible for most functions of cellular metabolism and a mediator between dietary and endogenous sources of energy for extrahepatic tissues. In this context, adenosine-monophosphate- (AMP-) activated protein kinase (AMPK) constitutes an intrahepatic energy sensor regulating physiological energy dynamics by limiting anabolism and stimulating catabolism, thus increasing ATP availability. This is achieved by mechanisms involving direct allosteric activation and reversible phosphorylation of AMPK, in response to signals such as energy status, serum insulin/glucagon ratio, nutritional stresses, pharmacological and natural compounds, and oxidative stress status. Reactive oxygen species (ROS) lead to cellular AMPK activation and downstream signaling under several experimental conditions. Thyroid hormone (L-3,3′,5-triiodothyronine, T3) administration, a condition that enhances liver ROS generation, triggers the redox upregulation of cytoprotective proteins affording preconditioning against ischemia-reperfusion (IR) liver injury. Data discussed in this work suggest that T3-induced liver activation of AMPK may be of importance in the promotion of metabolic processes favouring energy supply for the induction and operation of preconditioning mechanisms. These include antioxidant, antiapoptotic, and anti-inflammatory mechanisms, repair or resynthesis of altered biomolecules, induction of the homeostatic acute-phase response, and stimulation of liver cell proliferation, which are required to cope with the damaging processes set in by IR.

Modulation of Nrf2 by Olive Oil and Wine Polyphenols and Neuroprotection

“…The principal class of generated radical species is ROS. They can be defined as oxygen-containing molecules or fragments with one or more unpaired electrons in atomic or molecular orbitals [ 44 , 45 , 46 ]. ROS generation can originate through external sources such as ultraviolet rays, high-energy irradiation, xenobiotic metabolism, and the redox-cycling of quinones, ions, metals, and nitroaromatics [ 42 , 47 , 48 ].…”

(Healthy) Ageing: Focus on Iodothyronines

“…It is known that disturbances in redox homeostasis lead to ischemia-reperfusion injury [95]. T3 prevents reperfusion injury by enhancing ROS production, thus triggering the redox upregulation of cytoprotective proteins affording preconditioning against ischemia-reperfusion injury in liver [96], heart [97], and kidney [98].…”

“…Injection of T3 into euthyroid rats results in T2 accumulation in serum and liver within 24 hours, coinciding with a peak in metabolic rate [111]. Thus, a possibility that cannot entirely be excluded is that part of the presumed T3-mediated effects in studies, in which deiodinase activity is not inhibited, [14,95] are not due to T3 itself.…”

Eruca sativa Essential Oil Protects upon Hyperthyroidism Induced Damages in Rat

“…Moreover, this thyroid dysfunction can be also associated with hyper-metabolic state which caused mainly by oxidative stress which induced damage to molecules, then affected many organs. It seems that when thyroid hormones increase metabolic systems of the body in general, the resulting increase in reactive oxygen types inevitably leads to lipid peroxidation [25]. On the other hand, hyperthyroidism leads to changes in both oxidant and antioxidant systems.…”