Research Report
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World J Gastroenterol. Dec 14, 2014; 20(46): 17416-17425
Published online Dec 14, 2014. doi: 10.3748/wjg.v20.i46.17416
T3-induced liver AMP-activated protein kinase signaling: Redox dependency and upregulation of downstream targets
Luis A Videla, Virginia Fernández, Pamela Cornejo, Romina Vargas, Paula Morales, Juan Ceballo, Alvaro Fischer, Nicolás Escudero, Oscar Escobar
Luis A Videla, Virginia Fernández, Pamela Cornejo, Romina Vargas, Paula Morales, Juan Ceballo, Alvaro Fischer, Nicolás Escudero, Oscar Escobar, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile
Pamela Cornejo, School of Medical Technology, Faculty of Medicine, Diego Portales University, Ejército 141, Santiago, Chile
Author contributions: Videla LA designed the research and wrote the article with the input of Fernández V, Cornejo P and Vargas R; Biochemical and molecular analyses were performed by Vargas R, Morales P, Ceballo J, Fischer A, Escudero N and Escobar O; all authors have approved the final manuscript and declare that there is no conflict in interest that could be perceived as prejudicing the impartiality of the research reported.
Supported by National Commission for Scientific and Technological Research Grant No. 1120034
Correspondence to: Luis A Videla, Professor, Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia Avenue 1027, Chile. lvidela@med.uchile.cl
Telephone: +56-2-29786256 Fax: +56-2-27372783
Received: April 22, 2014
Revised: June 6, 2014
Accepted: July 29, 2014
Published online: December 14, 2014
Processing time: 240 Days and 14 Hours
Abstract

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 (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 T3. Measurements included plasma and liver 8-isoprostane and serum β-hydroxybutyrate levels (ELISA), hepatic levels of mRNAs (qPCR), proteins (Western blot), and phosphorylated AMPK (ELISA).

RESULTS: T3 upregulates AMPK signaling, including the upstream kinases Ca2+-calmodulin-dependent protein kinase kinase-β and 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-CoA 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-γ co-activator-1α and that of the fatty acid oxidation (FAO)-related enzymes CPT-1α, acyl-CoA oxidase 1, and acyl-CoA thioesterase 2. Under these conditions, T3 induced a significant increase in the serum levels of β-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 T3 preconditioning against ischemia-reperfusion injury.

Keywords: Liver; Thyroid hormone; N-acetylcysteine; AMP-activated protein kinase; Fatty acid oxidation

Core tip: This work investigated the redox dependency and promotion of downstream targets in thyroid hormone (T3)-induced AMP-activated protein kinase (AMPK) signaling. T3 upregulates AMPK with T3-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-1α activation and higher expression of peroxisome proliferator-activated receptor-γ co-activator-1α and that of the fatty acid oxidation (FAO)-related enzymes. This lead to enhancement in the serum levels of β-hydroxybutyrate, a surrogate marker for hepatic FAO, which represent a key molecular mechanism regulating energy dynamics to limit metabolic stresses.