title: Treatment with a novel oleic-acid-dihydroxyamphetamine conjugation ameliorates non-alcoholic fatty liver disease in obese Zucker rats.
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.
authors.affiliation: Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, 29010 Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Decara
authors.affiliation: Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, 29010 Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Pavón
authors.affiliation: Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, 29010 Spain CIBER de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Madrid, 28029 Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Suárez
authors.affiliation: Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, 29010 Spain CIBER de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Madrid, 28029 Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Romero-Cuevas
authors.affiliation: Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, 29010 Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Baixeras
authors.affiliation: Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, 29010 Spain.
authors.forename: Mariam
authors.initials: M
authors.lastname: Vázquez
authors.affiliation: Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, 29010 Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Rivera
authors.affiliation: Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, 29010 Spain.
authors.forename: Ana L
authors.initials: AL
authors.lastname: Gavito
authors.affiliation: Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Neurosciences Program, Barcelona, 08003 Spain Facultat de Ciencies de la Salut i de la Vida, Universitat Pompeu Fabra (CEXS-UPF), Barcelona, 08002 Spain.
authors.forename: Bruno
authors.initials: B
authors.lastname: Almeida
authors.affiliation: Departamento de Química Biológica y Modelización Molecular, Instituto de Química Avanzada de Cataluña (IQAC-CSIC), Barcelona, 08034 Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Joglar
authors.affiliation: CIBER de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Madrid, 28029 Spain Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Neurosciences Program, Barcelona, 08003 Spain Facultat de Ciencies de la Salut i de la Vida, Universitat Pompeu Fabra (CEXS-UPF), Barcelona, 08002 Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: de la Torre
authors.affiliation: Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, 29010 Spain CIBER de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Madrid, 28029 Spain fernando.rodriguez@ibima.eu antonia.serrano@ibima.eu.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodríguez de Fonseca
authors.affiliation: Unidad Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Málaga, 29010 Spain CIBER de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Madrid, 28029 Spain fernando.rodriguez@ibima.eu antonia.serrano@ibima.eu.
authors.forename: Antonia
authors.initials: A
authors.lastname: Serrano
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003846:Deoxyepinephrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects; D005838:Genotype; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D019301:Oleic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D047493:PPAR alpha; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D014157:Transcription Factors; D019301:Oleic Acid; C023492:alpha-methyldopamine; D003846:Deoxyepinephrine
keywords: CB1; Cannabinoid type 1 receptor; Non-alcoholic fatty liver disease; Obesity; PPAR-α; Peroxisome proliferator activated-receptor α; Zucker rats