Treatment with a novel oleic-acid-dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats.

Decara, Juan M.; Pavón, Francisco Javier; Suárez, Juan; Romero-Cuevas, Miguel; Baixeras, Elena; Vázquez, Mariam; Rivera, Patricia; Gavito, Ana L.; Almeida Cotrim, Bruno; Joglar Tamargo, Jesús; Torre Fornell, Rafael de la; Rodríguez de Fonseca, Fernando; Serrano, Antonia

Treatment with a novel oleic-acid-dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats.

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dc.contributor.author Decara, Juan M.ca
dc.contributor.author Pavón, Francisco Javierca
dc.contributor.author Suárez, Juanca
dc.contributor.author Romero-Cuevas, Miguelca
dc.contributor.author Baixeras, Elenaca
dc.contributor.author Vázquez, Mariamca
dc.contributor.author Rivera, Patriciaca
dc.contributor.author Gavito, Ana L.ca
dc.contributor.author Almeida Cotrim, Brunoca
dc.contributor.author Joglar Tamargo, Jesúsca
dc.contributor.author Torre Fornell, Rafael de laca
dc.contributor.author Rodríguez de Fonseca, Fernandoca
dc.contributor.author Serrano, Antoniaca
dc.date.accessioned 2016-02-17T12:33:26Z
dc.date.available 2016-02-17T12:33:26Z
dc.date.issued 2015
dc.description.abstract Fatty liver disease is one of the main hepatic complications associated with obesity. To date, there are no effective treatments for this pathology apart from the use of classical fibrates. In this study, we have characterized the in vivo effects of a novel conjugation of oleic acid with an amphetamine derivative (OLHHA) in an animal model of genetic obesity. Lean and obese Zucker rats received a daily intraperitoneal administration of OLHHA (5 mg kg(-1)) for 15 days. Plasma and liver samples were collected for the biochemical and molecular biological analyses, including both immunohistochemical and histological studies. The expression of key enzymes and proteins that are involved in lipid metabolism and energy homeostasis was evaluated in the liver samples. The potential of OLHHA to produce adverse drug reactions or toxicity was also evaluated through the monitoring of interactions with hERG channel and liver cytochrome. We found that OLHHA is a drug with a safe pharmacological profile. Treatment for 15 days with OLHHA reduced the liver fat content and plasma triglyceride levels, and this was accompanied by a general improvement in the profile of plasma parameters related to liver damage in the obese rats. A decrease in fat accumulation in the liver was confirmed using histological staining. Additionally, OLHHA was observed to exert anti-apoptotic effects. This hepatoprotective activity in obese rats was associated with an increase in the mRNA and protein expression of the cannabinoid type 1 receptor and a decrease in the expression of the lipogenic enzymes FAS and HMGCR primarily. However, changes in the mRNA expression of certain proteins were not associated with changes in the protein expression (i.e. L-FABP and INSIG2). The present results demonstrate that OLHHA is a potential anti-steatotic drug that ameliorates the obesity-associated fatty liver and suggest the potential use of this new drug for the treatment of non-alcoholic fatty liver disease.ca
dc.description.sponsorship The present study has been supported by the following grants: Ministerio de Economía y Competitividad and Instituto de Salud Carlos III (PI13/02261); Instituto de Salud Carlos III and EU-ERDF (Subprograma RETICS Red de Trastornos Adictivos RD12/0028/0001 and Consortium CIBER-Obn CB06/03/1008); Junta de Andalucía-Consejería de Economía, Innovación y Ciencia (PI45403 and CTS-8221); Junta de Andalucía-Consejería de Igualdad, Salud y Políticas Sociales (PI-0823-2012 and PI-0337-2012). F.J.P., J.S. and A.S. hold a ‘Miguel Servet’ research contract from Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER/EU-ERDF) (CP14/00212, CP12/03109 and CP14/00173, respectively).
dc.format.mimetype application/pdfca
dc.identifier.citation Decara JM, Pavón FJ, Suárez J, Romero-Cuevas M, Baixeras E, Vázquez M et al. Treatment with a novel oleic-acid-dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats. Dis Model Mech. 2015 Oct 1;8(10):1213-25. DOI: 10.1242/dmm.019919.ca
dc.identifier.doi http://dx.doi.org/10.1242/dmm.019919
dc.identifier.issn 1213-1225
dc.identifier.uri http://hdl.handle.net/10230/25851
dc.language.iso engca
dc.publisher Company of Biologistsca
dc.relation.ispartof Disease Models & Mechanisms. 2015 Oct 1;8(10):1213-25
dc.rights This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.ca
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.rights.uri http://creativecommons.org/licenses/by/3.0/ca
dc.subject.other Cannabinoides -- Receptorsca
dc.subject.other Fetge -- Malaltiesca
dc.subject.other Obesitatca
dc.title Treatment with a novel oleic-acid-dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats.ca
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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