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

Abstract

Liver preconditioning (PC), defined as an enhanced tolerance to injuring stimuli induced by previous specific maneuvers triggering beneficial functional and molecular changes, is of crucial importance in human liver transplantation and major hepatic resection. For these reasons, numerous PC strategies have been evaluated in experimental models of ischemia-reperfusion liver injury, which have not been transferred to clinical application due to side effects, toxicity and difficulties in implementation, with the exception of the controversial ischemic PC. In recent years, our group has undertaken the assessment of alternate experimental liver PC protocols that might have application in the clinical setting. These include thyroid hormone (T3), n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA), or iron, which suppressed liver damage due to the 1 h ischemia-20 h reperfusion protocol. T3, n-3 LCPUFA and iron are hormetic agents that trigger biologically beneficial effects in the low-dose range, whose multifactorial mechanisms of action are discussed in the work.

The impact of high fat diets on physiological changes in euthyroid and thyroid altered rats

“…The elevation of these liver enzymes values may be indicative of some liver impairment, or possibly damage. Liver damage resulting from underlying cellular death is often associated with cholestasis, drug-induced injury and obesity [34]. The liver and the thyroid gland are intricately connected in lipid metabolism as well as in the maintenance of homeostasis.…”

Misregulation of PPAR Functioning and Its Pathogenic Consequences Associated with Nonalcoholic Fatty Liver Disease in Human Obesity

“…Liver LCPUFA n-3 depletion in obesity may be related to higher utilization due the prevailing high oxidative stress status [57, 72] (Figure 1A), a contention that is supported by the significant inverse correlation established between liver phospholipid LCPUFA n-3 content and serum F 2 -isoprostane levels, as index of free-radical activity (Figure 2(a)). Under these conditions, the nonenzymatic oxidative decomposition of LCPUFA n-3 to J 3 -isoprostane derivatives [73] can occur; however, utilization of LCPUFA n-3 by cyclooxygenase-2/5-lipoxygenase pathway and/or the cytochrome P450 NADPH-dependent epoxygenase system [74] cannot be discarded. In addition to enhanced liver LCPUFA n-3 utilization, depletion of LCPUFA n-3 in NAFLD is associated with defective hepatic capacity for desaturation of the LCPUFA n-3 essential precursor α -linolenic acid ( α -LA, 18:3n-3).…”

Causal role of oxidative stress in unfolded protein response development in the hyperthyroid state

“…Cell protection, survival, and functional recovery are elicited by the administration of low doses of T 3 to experimental animals [7]. In the liver, these features are coupled to the activation of the redox-sensitive transcription factors nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), activating protein 1, or nuclear factor-erythroid 2-related factor 2 (Nrf2) upon oxidative stress development, with concurrence of AMPK upregulation for energy supply (Fig.…”

“…2 biomolecules during IR and repletion of ATP levels reduced in the ischemic phase [7]. In agreement with this view, T 3 administration upregulates liver AMP-activated protein kinase (AMPK) [10], a sensor of energy status supporting cellular energy homeostasis [11].…”

“…Accordingly, liver PC is confronted with a major energy requirement to cope with ATP demands for operation of most of the PC mechanisms outlined above, plus those for repair and resynthesis of altered 2 biomolecules during IR and repletion of ATP levels reduced in the ischemic phase [7]. In agreement with this view, T 3 administration upregulates liver AMP-activated protein kinase (AMPK) [10], a sensor of energy status supporting cellular energy homeostasis [11].…”