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EBP-B AND PPAR-A IN THE REGULATION OF CARDIAC FATTY ACID-RESPONSIVE GENES
Workshop V-8 - Basic Science and Vascular Biology: Cellular Lipid Metabolism Abstract: 1045 Citation: Atherosclerosis Supplement 2009, Vol. 10, Issue 2
COORDINATED FUNCTION OF C/EBP-Ǻ AND PPAR-ǹ IN THE REGULATION OF CARDIAC FATTY ACID-RESPONSIVE GENES J Suzuki1, M Fujii1, M Ueno2, T Kimura1, M Imagawa1, Y Zenimaru1, S Takahashi1, H Kimura1, F Kraemer2, I Miyamori1 1
Medicine, Fukui University, Fukui; 2Medicine, Stanford University, Stanford, CA
Objectives: Excess fatty acids (FA) evoke cardiac lipotoxicity and dysfunction. The objective was to explore cardiac gene expression pathways in response to FA load in hormone-sensitive lipase-overexpressing (Tg) mice and fasted wildtype (Wt) mice. Methods: Putative FA-responsive genes were extracted from overlapping genes whose expression was induced in both Tg and fasted Wt mice from microarray data and analyzed. Cardiomyocyte precursor P19CL6 cells were incubated with FA in the absence or presence of siRNA targeted to C/EBP-ȕ or PPAR-Į and gene expression analyzed by qRT-PCR. Genes were also analyzed in hearts of fed or 24h-fasted PPAR-Į-null mice. Results: 19 overlapping genes were identified, including 7 transcription factors (C/EBP-ȕ etc.), expression of 6 of these 7 genes was increased with FA in vitro. Both C/EBP-ȕ and PPAR-Į siRNA inhibited FA-induced expression of c-fos and Cyr61. C/EBP-ȕ siRNA decreased expression of PPAR-Į, whereas PPAR-Į siRNA increased expression of C/EBP-ȕ, suggesting that C/EBP-ȕ positively regulates PPAR-Į expression. Mitochondrial HMG-CoA synthase, uncoupling protein 3 and adipose differentiation-related protein were decreased by either C/EBP-ȕ or PPAR-Į siRNA. In addition, induction of these 3 genes was blunted in fasted PPARĮ-null mice. Conclusions: C/EBP-ȕ and PPAR-Į coordinately regulate expression of FA-responsive genes involved in cardiac FA metabolism. Funding: Supported by a grant from the Japan Society for the Promotion of Science.
COORDINATED FUNCTION OF C/EBP-Ǻ AND PPAR-ǹ IN THE REGULATION OF CARDIAC FATTY ACID-RESPONSIVE GENES J Suzuki1, M Fujii1, M Ueno2, T Kimura1, M Imagawa1, Y Zenimaru1, S Takahashi1, H Kimura1, F Kraemer2, I Miyamori1 1
Medicine, Fukui University, Fukui; 2Medicine, Stanford University, Stanford, CA
Objectives: Excess fatty acids (FA) evoke cardiac lipotoxicity and dysfunction. The objective was to explore cardiac gene expression pathways in response to FA load in hormone-sensitive lipase-overexpressing (Tg) mice and fasted wildtype (Wt) mice. Methods: Putative FA-responsive genes were extracted from overlapping genes whose expression was induced in both Tg and fasted Wt mice from microarray data and analyzed. Cardiomyocyte precursor P19CL6 cells were incubated with FA in the absence or presence of siRNA targeted to C/EBP-ȕ or PPAR-Į and gene expression analyzed by qRT-PCR. Genes were also analyzed in hearts of fed or 24h-fasted PPAR-Į-null mice. Results: 19 overlapping genes were identified, including 7 transcription factors (C/EBP-ȕ etc.), expression of 6 of these 7 genes was increased with FA in vitro. Both C/EBP-ȕ and PPAR-Į siRNA inhibited FA-induced expression of c-fos and Cyr61. C/EBP-ȕ siRNA decreased expression of PPAR-Į, whereas PPAR-Į siRNA increased expression of C/EBP-ȕ, suggesting that C/EBP-ȕ positively regulates PPAR-Į expression. Mitochondrial HMG-CoA synthase, uncoupling protein 3 and adipose differentiation-related protein were decreased by either C/EBP-ȕ or PPAR-Į siRNA. In addition, induction of these 3 genes was blunted in fasted PPARĮ-null mice. Conclusions: C/EBP-ȕ and PPAR-Į coordinately regulate expression of FA-responsive genes involved in cardiac FA metabolism. Funding: Supported by a grant from the Japan Society for the Promotion of Science.