Atherosclerosis 212 (2010) 268–273 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis Cysteinemia, rather than homocysteinemia, is associated with plasma apolipoprotein A-I levels in hyperhomocysteinemia Lipid metabolism in cystathionine -synthase deficiency Mario Nu ˜ no-Ayala a , Natalia Guillén a,g , María A. Navarro a,g , Jose M. Lou-Bonafonte b , Carmen Arnal e,g , Sonia Gascón a,g , Cristina Barranquero a,g , Javier Godino a , María Royo-Ca ˜ nas a , Alfonso J. Sarría c,g , Mario A. Guzmán a , Esther Hernandez d , Miguel A. Bregante d , María A. García-Gimeno f , Jesús Osada a,g,∗ a Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Veterinaria, Instituto Aragonés de Ciencias de la Salud (Universidad de Zaragoza-Salud del Gobierno de Aragón), Spain b Departamento de Farmacología y Fisiología, Facultad de Ciencias de la Salud y del Deporte, Universidad de Zaragoza, Spain c Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias de la Salud y del Deporte, Universidad de Zaragoza, Spain d Departamento de Farmacología y Fisiología, Facultad de Veterinaria, Universidad de Zaragoza, Spain e Departamento de Patología Animal, Facultad de Veterinaria, Universidad de Zaragoza, Spain f Departamento de Química Analítica, Facultad de Veterinaria, Universidad de Zaragoza, Spain g CIBER de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Spain article info Article history: Received 27 August 2009 Received in revised form 15 April 2010 Accepted 23 April 2010 Available online 26 May 2010 Keywords: Apolipoproteins Cystathionine -synthase deficient mice Cysteine Homocysteine Methionine abstract Objective: Genetic and dietary hyperhomocysteinemia has been found to decrease high density lipopro- teins (HDL) and their apolipoprotein A1 (APOA1). To test the hypothesis that the presence of cysteine could normalize HDL levels in hyperhomocysteinemic cystathionine -synthase (Cbs)-deficient mice and that the inclusion of glycine would block this effect. Methods: Lipids and HDL cholesterol were studied in Cbs-deficient mice and wild-type animals fed a low-methionine diet supplemented with cysteine and glycine and in Cbs-deficient mice on the same diet supplemented only with cysteine. Results: Triglyceride and homocysteine levels were significantly decreased and increased, respectively in Cbs-deficient mice irrespective of treatment. However, plasma cholesterol, glucose and APOA1 were significantly decreased in homozygous Cbs-deficient mice when they received the cysteine and glycine- enriched beverage. This group of mice also showed decreased mRNA levels and increased hepatic content of APOA1 protein, the latter increase was observed in endothelial cells. A significant, inverse relationship was observed between plasma and hepatic APOA1 concentrations while a positive one was found between plasma levels of cysteine and APOA1. Conclusion: These data suggest an altered hepatic management of APOA1 and that cysteine may be involved in the control of this apolipoprotein at this level. Overall these findings represent a new aspect of dietary regulation of HDL at the hepatic transendothelial transport. © 2010 Elsevier Ireland Ltd. All rights reserved. Abbreviations: Apo, apolipoprotein; CBS, cystathionine -synthase; FPLC, fast protein liquid chromatography; GSH, Glutathione; Hcy, homocysteine; HDL, high density lipoproteins; IL-6, interleukin 6; MCP-1, monocyte chemotactic protein-1; PCR, polymerase chain reaction; RT, reverse transcriptase; TG, triglycerides; TNF, tumor necrosis factor ; tPAI-1, tissue plasminogen activator inhibitor 1; UPR, unfolding protein response. ∗ Corresponding author at: Department of Biochemistry and Molecular Biology, Veterinary School, University of Zaragoza, Miguel Servet, 177, E-50013 Zaragoza, Spain. Tel.: +34 976 761644; fax: +34 976 761612. E-mail address: Josada@unizar.es (J. Osada). 1. Introduction Homocysteine (Hcy) was first implicated as a risk factor for cardiovascular disease in the late 60s when it was noticed that homocystinuric patients displayed thrombosis that increased mortality from vascular diseases [1]. Several epidemiological stud- ies have shown an association between elevated plasma Hcy and vascular disease, and hyperhomocysteinemia is considered as an independent risk factor for cardiovascular diseases [2,3]. Indeed, a 5 M increase in plasma Hcy is associated with a 42% increased risk of ischemic heart disease, and with a 60% of stroke [3]. 0021-9150/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.04.028