title: AICAR Protects against High Palmitate/High Insulin-Induced Intramyocellular Lipid Accumulation and Insulin Resistance in HL-1 Cardiac Cells by Inducing PPAR-Target Gene Expression.
abstract: Here we studied the impact of 5-aminoimidazole-4-carboxamide riboside (AICAR), a well-known AMPK activator, on cardiac metabolic adaptation. AMPK activation by AICAR was confirmed by increased phospho-Thr(172)-AMPK and phospho-Ser(79)-ACC protein levels in HL-1 cardiomyocytes. Then, cells were exposed to AICAR stimulation for 24 h in the presence or absence of the AMPK inhibitor Compound C, and the mRNA levels of the three PPARs were analyzed by real-time RT-PCR. Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK. Next, we exposed HL-1 cells to high palmitate/high insulin (HP/HI) conditions either in presence or in absence of AICAR, and we evaluated the expression of selected PPAR-targets genes. HP/HI induced insulin resistance and lipid storage was accompanied by increased Cd36, Acot1, and Ucp3 mRNA levels. AICAR treatment induced the expression of Acadvl and Glut4, which correlated to prevention of the HP/HI-induced intramyocellular lipid build-up, and attenuation of the HP/HI-induced impairment of glucose uptake. These data support the hypothesis that AICAR contributes to cardiac metabolic adaptation via regulation of transcriptional mechanisms.
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rodríguez-Calvo
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, Biomedicine Institute of University of Barcelona (IBUB), Pediatric Research Institute-Sant Joan de Déu Hospital and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Faculty of Pharmacy, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
authors.affiliation: Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, "Sant Joan" University Hospital, Pere Virgili Health Research Institute (IISPV) and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Faculty of Medicine and Health Sciences, Rovira i Virgili University, Sant Llorenç 21, 4301 Reus, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Masana
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands.
authors.forename: Dietbert
authors.initials: D
authors.lastname: Neumann