Thyroid hormone suppresses ischemia-reperfusion-induced liver NLRP3 inflammasome activation: Role of AMP-activated protein kinase

- T3 confers liver preconditioning (PC) against ischemia-reperfusion (IR).
- T3 suppresses the inflammation associated with IR-induced NLRP3 and IL-1β induction.
- Inhibition of AMP-activated protein kinase (AMPK) recovers inflammasome upregulation.
- AMPK has a causal role on liver PC by T3 promoting energy dynamics and cell survival.

Thyroid hormone (T3) induces liver preconditioning (PC) against ischemia-reperfusion (IR), a response energetically supported by AMP-activated protein kinase (AMPK) upregulation. The aim of this work is to evaluate the influence of T3 on IR-induced liver NLRP3 inflammasome activation and the relevance of AMPK activity on liver injury by the use of the AMPK inhibitor compound C (CC). Male Sprague-Dawley rats were given 0.1 mg T3/kg (time zero) and 10 mg CC/kg (time zero and 24 h) or the respective vehicles, and subjected to 1 h ischemia-20 h reperfusion 48 h after hormone treatment. Measurements included parameters of liver injury, hepatic levels of mRNAs (qPCR) and proteins (Western Blot or ELISA). IR induced substantial distortion of liver architecture, hepatocyte necrosis, and neutrophil infiltration with increased serum aspartate aminotransferase (AST) levels. T3 suppressed IR liver injury and AST enhancement, effects that were reverted by CC. Concomitantly, IR-induced liver mRNA and protein expression of NLRP3 and interleukin-1β (IL-1β) were restrained by T3, whereas CC eliminated T3-dependent PC. In conclusion, in vivo T3 administration triggers liver PC against IR injury by suppressing the inflammatory response associated with hepatic NLRP3 and IL-1β upregulation, with AMPK playing a causal role regulating energy dynamics to upkeep PC.

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