Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 398, Issue 3, Pages 495-499Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2010.06.106
Keywords
AMPK; Acetyl-CoA carboxylase; Nuclear respiratory factor-1; Fatty acid beta-oxidation; Transcriptional regulation
Categories
Funding
- South African National Research Foundation
- Medical Research Council
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The cardiac-enriched isoform of acetyl-CoA carboxylase (ACC beta) produces malonyl-CoA, a potent inhibitor of carnitine palmitoyltransferase-1. AMPK inhibits ACC beta activity, lowering malonyl-CoA levels and promoting mitochondrial fatty acid beta-oxidation. Previously, AMPK increased promoter binding of nuclear respiratory factor-1 (NRF-1), a pivotal transcriptional modulator controlling gene expression of mitochondria! proteins. We therefore hypothesized that NRF-1 inhibits myocardial ACC beta promoter activity via AMPK activation. A human ACC beta promoter-luciferase construct was transiently transfected into neonatal cardiomyocytes +/- a NRF-1 expression construct. NRF-1 overexpression decreased ACC beta gene promoter activity by 71 +/- 4.6% (p < 0.001 vs. control). Transfections with 5'-end serial promoter deletions revealed that NRF-1-mediated repression of ACC beta was abolished with a pPII beta-18/+65-Luc deletion construct. AMPK activation dose-dependently reduced ACC beta promoter activity, while NRF-1 addition did not further decrease it. We also investigated NRF-1 inhibition in the presence of upstream stimulatory factor 1 (USF1), a known transactivator of the human ACC beta gene promoter. Here NRF-1 blunted USF1-dependent induction of ACC beta promoter activity by 58 +/- 7.5% (p < 0.001 vs. control), reversed with a dominant negative NRF-1 construct. NRF-1 also suppressed endogenous USF1 transcriptional activity by 55 +/- 6.2% (p < 0.001 vs. control). This study demonstrates that NRF-1 is a novel transcriptional inhibitor of the human ACC beta gene promoter in the mammalian heart. Our data extends AMPK regulation of ACC beta to the transcriptional level. (C) 2010 Elsevier Inc. All rights reserved.
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