NEFA (non-esterified ‘free’ fatty acid)-mediated lipotoxicity plays a critical role in the pathogenesis of NASH (non-alcoholic steatohepatitis). In the light of the growing need for new therapeutic options for NASH, we investigated the action of A2aR (adenosine A2a receptor) stimulation against lipotoxicity. The effects of the A2aR agonist CGS21680 [2-p-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxyamidoadenosine] were evaluated ‘in vitro’ in liver cells exposed to SA (stearic acid) and ‘in vivo’ in rats with NASH induced by 8 weeks of feeding with an MCD diet (methionine/choline-deficient diet). In cultured hepatocytes, SA promoted apoptosis by inducing MKK4 (mitogen-activated protein kinase kinase 4)/SEK1 (stress-activated protein kinase/extracellular-signal-regulated kinase kinase-1) and JNK-1/2 (c-Jun N-terminal kinase-1/2) activation. CGS21680 addition prevented JNK-1/2 activation and reduced apoptosis without interfering with lipid accumulation. CGS21680 action required PI3K (phosphoinositide 3-kinase)/Akt-mediated block of MKK4/SEK1. Consistently, PI3K inhibition with wortmannin abolished the cytoprotective action of CGS21680 and reverted MKK4 inhibition. SA lipotoxicity was also prevented by transfecting HTC cells with a specific MKK4/SEK1 siRNA (small interfering RNA). In rats receiving the MCD diet, the development of NASH was associated with MKK4/SEK1 and JNK-1/2 activation. CGS21680 (0.5 mg/kg of body weight, intraperitoneal) administration to MCD-fed rats prevented JNK-1/2 activation by acting on MKK4/SEK1. CGS21680 also effectively reduced NASH-associated ALT (alanine aminotransferase) release, hepatocyte apoptosis, liver inflammation and fibrosis without affecting hepatic steatosis. Taken together, these results demonstrate that, by inhibiting JNK-1/2, A2aR stimulation reduces lipotoxicity and ameliorates NASH, giving a rationale to investigate A2aR agonists as possible new therapeutic agents in preventing fatty liver progression to NASH.
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Research Article|
May 16 2012
Adenosine A2a receptor stimulation prevents hepatocyte lipotoxicity and non-alcoholic steatohepatitis (NASH) in rats
Chiara Imarisio;
Chiara Imarisio
*Department of Health Sciences, University ‘A. Avogadro’, Novara 28100, Italy
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Elisa Alchera;
Elisa Alchera
*Department of Health Sciences, University ‘A. Avogadro’, Novara 28100, Italy
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Salvatore Sutti;
Salvatore Sutti
*Department of Health Sciences, University ‘A. Avogadro’, Novara 28100, Italy
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Guido Valente;
Guido Valente
*Department of Health Sciences, University ‘A. Avogadro’, Novara 28100, Italy
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Francesca Boccafoschi;
Francesca Boccafoschi
†Department of Translational Medicine, University ‘A. Avogadro’, Novara 28100, Italy
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Emanuele Albano;
Emanuele Albano
*Department of Health Sciences, University ‘A. Avogadro’, Novara 28100, Italy
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Rita Carini
*Department of Health Sciences, University ‘A. Avogadro’, Novara 28100, Italy
Correspondence: Professor Rita Carini (email [email protected]).
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Publisher: Portland Press Ltd
Received:
October 04 2011
Revision Received:
January 26 2012
Accepted:
March 22 2012
Accepted Manuscript online:
March 22 2012
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2012 Biochemical Society
2012
Clin Sci (Lond) (2012) 123 (5): 323–332.
Article history
Received:
October 04 2011
Revision Received:
January 26 2012
Accepted:
March 22 2012
Accepted Manuscript online:
March 22 2012
Citation
Chiara Imarisio, Elisa Alchera, Salvatore Sutti, Guido Valente, Francesca Boccafoschi, Emanuele Albano, Rita Carini; Adenosine A2a receptor stimulation prevents hepatocyte lipotoxicity and non-alcoholic steatohepatitis (NASH) in rats. Clin Sci (Lond) 1 September 2012; 123 (5): 323–332. doi: https://doi.org/10.1042/CS20110504
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