AMPK activation represses the human gene promoter of the cardiac isoform of acetyl-CoA carboxylase: Role of nuclear respiratory factor-1

作者：Adam Tasneem; Opie Lionel H; Essop M Faadiel^*

来源：Biochemical and Biophysical Research Communications, 2010, 398(3): 495-499.

DOI：10.1016/j.bbrc.2010.06.106

• AMPK
• Acetyl-CoA carboxylase
• Nuclear respiratory factor-1
• Fatty acid beta-oxidation
• Transcriptional regulation

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.

• 出版日期2010-7-30