title: Short and long term in vivo effects of Cyclosporine A and Sirolimus on genes and proteins involved in lipid metabolism in Wistar rats.
abstract: OBJECTIVE
  Cyclosporine A (CsA) and sirolimus (SRL) are immunosuppressive agents (IA) associated with new onset diabetes after transplantation and dyslipidemia. We aim to evaluate the molecular effects of CsA (5mg/kg/day) and SRL (1mg/kg/day) treatment for 3 and 9weeks on lipid metabolism, in Wistar rats.
  
  
  METHODS
  Lipolysis was evaluated in isolated adipocytes, while triglycerides (TG) and non-esterified fatty acid (NEFA) were measured in serum. Gene and protein expression involved in lipid metabolism was assessed in adipose tissue and liver.
  
  
  RESULTS
  CsA and SRL treatments of rats for 3 and 9weeks increased isoproterenol-stimulated lipolysis by 5-9 fold and 4-6 fold in isolated adipocytes, respectively. While CsA increased adipocyte weight and diameter, as well as NEFA and TG levels in circulation after 9weeks, SRL treatment caused ectopic deposition of TG in the liver after 3weeks. Moreover, ACC1 and FAS protein expression was increased after 3weeks (>100%, p<0.01), while HSL was increased after 9weeks of CsA treatment. On the other hand, SRL decreased the expression of lipogenic genes, including ACC1 (50%, p<0.05), lipin1 (25%, p<0.05), PPAR-γ (42%, p<0.05) and SCD1 (80%, p<0.001) in adipose tissue, after 3weeks of treatment.
  
  
  CONCLUSIONS
  The effects of both IAs on expression of lipolytic and lipogenic genes suggest that these agents influence lipid metabolism, thus contributing to the dyslipidemia observed during immunosuppressive therapy.
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-517 Coimbra, Portugal.
authors.forename: Patrícia C
authors.initials: PC
authors.lastname: Lopes
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-517 Coimbra, Portugal.
authors.forename: Amelia
authors.initials: A
authors.lastname: Fuhrmann
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal; Institute for Nuclear Sciences Applied to Heath-ICNAS, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: José
authors.initials: J
authors.lastname: Sereno
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-517 Coimbra, Portugal.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Espinoza
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-517 Coimbra, Portugal; Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Pereira
authors.affiliation: Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Jan W
authors.initials: JW
authors.lastname: Eriksson
authors.affiliation: Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Flávio
authors.initials: F
authors.lastname: Reis
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, 3000-517 Coimbra, Portugal; The Portuguese Diabetes Association (APDP-ERC), 1250 203 Lisbon, Portugal. Electronic address: ecarvalh@cnc.uc.pt.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Carvalho
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics*; D008066:Lipolysis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D011506:Proteins; D016572:Cyclosporine; D020123:Sirolimus
keywords: Adipocytes; Dyslipidemia; Immunosuppressive therapy; Liver