T_3-induced liver AMP-activated protein kinase signaling:Redox dependency and upregulation of downstream targets

AIM: To investigate the redox dependency and promotion of downstream targets in thyroid hormone (T3)-induced AMP-activated protein kinase (AMPK) signaling as cellular energy sensor to limit metabolic stresses in the liver.

AIM:To investigate the redox dependency and promotion of downstream targets in thyroid hormone(T3)-induced AMP-activated protein kinase(AMPK)signaling as cellular energy sensor to limit metabolic stresses in the liver.METHODS:Fed male Sprague-Dawley rats were given a single ip dose of 0.1 mg T3/kg or T3 vehicle(Na OH0.1 N;controls)and studied at 8 or 24 h after treatment.Separate groups of animals received 500 mg N-acetylcysteine(NAC)/kg or saline ip 30 min prior T3.Measurements included plasma and liver 8-isoprostane and serumβ-hydroxybutyrate levels(ELISA),hepaticlevels of m RNAs(q PCR),proteins(Western blot),and phosphorylated AMPK(ELISA).RESULTS:T3 upregulates AMPK signaling,including the upstream kinases Ca2+-calmodulin-dependent protein kinase kinase-βand transforming growth factor-β-activated kinase-1,with T3-induced reactive oxygen species having a causal role due to its suppression by pretreatment with the antioxidant NAC.Accordingly,AMPK targets acetyl-Co A carboxylase and cyclic AMP response element binding protein are phosphorylated,with the concomitant carnitine palmitoyltransferase-1α(CPT-1α)activation and higher expression of peroxisome proliferator-activated receptor-γco-activator-1αand that of the fatty acid oxidation(FAO)-related enzymes CPT-1α,acyl-Co A oxidase 1,and acylCo A thioesterase 2.Under these conditions,T3 induced a significant increase in the serum levels ofβ-hydroxybutyrate,a surrogate marker for hepatic FAO.CONCLUSION:T3 administration activates liver AMPK signaling in a redox-dependent manner,leading to FAO enhancement as evidenced by the consequent ketogenic response,which may constitute a key molecular mechanism regulating energy dynamics to support T3preconditioning against ischemia-reperfusion injury.