T3-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 (T-3)-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 T-3/kg or T-3 vehicle (NaOH 0.1 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 T-3. Measurements included plasma and liver 8-isoprostane and serum beta-hydroxybutyrate levels (ELISA), hepatic levels of mRNAs (qPCR), proteins (Western blot), and phosphorylated AMPK (ELISA). RESULTS: T-3 upregulates AMPK signaling, including the upstream kinases Ca2+-calmodulin-dependent protein kinase kinase-beta and transforming growth factor-beta- activated kinase-1, with T-3-induced reactive oxygen species having a causal role due to its suppression by pretreatment with the antioxidant NAC. Accordingly, AMPK targets acetyl-CoA carboxylase and cyclic AMP response element binding protein are phosphorylated, with the concomitant carnitine palmitoyltransferase-1 alpha (CPT-1 alpha) activation and higher expression of peroxisome proliferator-activated receptor-gamma co-activator-1 alpha and that of the fatty acid oxidation (FAO)-related enzymes CPT-1 alpha, acyl-CoA oxidase 1, and acyl-CoA thioesterase 2. Under these conditions, T-3 induced a significant increase in the serum levels of beta-hydroxybutyrate, a surrogate marker for hepatic FAO. CONCLUSION: T-3 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 T-3 preconditioning against ischemia-reperfusion injury. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.