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Mol. Cell. Biol., Aug 1996, 4043-4051, Vol 16, No. 8
Copyright © 1996, American Society for Microbiology

Transcriptional control of a nuclear gene encoding a mitochondrial fatty acid oxidation enzyme in transgenic mice: role for nuclear receptors in cardiac and brown adipose expression

DL Disch, TA Rader, S Cresci, TC Leone, PM Barger, R Vega, PA Wood and DP Kelly
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

Expression of the gene encoding medium-chain acyl coenzyme A dehydrogenase (MCAD), a nuclearly encoded mitochondrial fatty acid beta- oxidation enzyme, is regulated in parallel with fatty acid oxidation rates among tissues and during development. We have shown previously that the human MCAD gene promoter contains a pleiotropic element (nuclear receptor response element [NRRE-1]) that confers transcriptional activation or repression by members of the nuclear receptor superfamily. Mice transgenic for human MCAD gene promoter fragments fused to a chloramphenicol acetyltransferase gene reporter were produced and characterized to evaluate the role of NRRE-1 and other promoter elements in the transcriptional control of the MCAD gene in vivo. Expression of the full-length MCAD promoter-chloramphenicol acetyltransferase transgene (MCADCAT.371) paralleled the known tissue- specific differences in mitochondrial beta-oxidation rates and MCAD expression. MCADCAT.371 transcripts were abundant in heart tissue and brown adipose tissue, tissues with high-level MCAD expression. During perinatal cardiac developmental stages, expression of the MCADCAT.371 transgene paralleled mouse MCAD mRNA levels. In contrast, expression of a mutant MCADCAT transgene, which lacked NRRE-1 (MCADCATdeltaNRRE-1), was not enriched in heart or brown adipose tissue and did not exhibit appropriate postnatal induction in the developing heart. Transient- transfection studies with MCAD promoter-luciferase constructs containing normal or mutant NRRE-1 sequences demonstrated that the nuclear receptor binding sequences within NRRE-1 are necessary for high- level transcriptional activity in primary rat cardiocytes. Electrophoretic mobility shift assays demonstrated that NRRE-1 was bound by several cardiac and brown adipose nuclear proteins and that these interactions required the NRRE-1 receptor binding hexamer sequences. Antibody supershift studies identified the orphan nuclear receptor COUP-TF as one of the endogenous cardiac proteins which bound NRRE-1. These results dictate an important role for nuclear receptors in the transcriptional control of a nuclear gene encoding a mitochondrial fatty acid oxidation enzyme and identify a gene regulatory pathway involved in cardiac energy metabolism.


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