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Communication

The Opposite Effect of c-Jun Transcription Factor on Apolipoprotein E Gene Regulation in Hepatocytes and Macrophages

1
Institute of Cellular Biology and Pathology “N. Simionescu”, 050568 Bucharest, Romania
2
Laboratory of Biochemistry, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, 71003 Crete, Greece
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(6), 1471; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061471
Received: 24 February 2019 / Revised: 18 March 2019 / Accepted: 20 March 2019 / Published: 23 March 2019
Apolipoprotein E (apoE) is mainly secreted by hepatocytes and incorporated into most plasma lipoproteins. Macrophages, which accumulate cholesterol and are critical for the development of the atherosclerotic plaque, are also an important, albeit smaller, apoE source. Distal regulatory elements control cell-specific activity of the apoE promoter: multienhancers (ME.1/2) in macrophages and hepatic control regions (HCR-1/2) in hepatocytes. A member of AP-1 cell growth regulator, c-Jun regulates the transcription of various apolipoproteins and proinflammatory molecules implicated in atherosclerosis. We aimed to investigate the effect of c-Jun on apoE expression in macrophages versus hepatocytes and to reveal the underlying molecular mechanisms. Herein we show that c-Jun had an opposite, cell-specific effect on apoE expression: downregulation in macrophages but upregulation in hepatocytes. Transient transfections using ME.2 deletion mutants and DNA pull-down (DNAP) assays showed that the inhibitory effect of c-Jun on the apoE promoter in macrophages was mediated by a functional c-Jun binding site located at 301/311 on ME.2. In hepatocytes, c-Jun overexpression strongly increased apoE expression, and this effect was due to c-Jun binding at the canonical site located at −94/−84 on the apoE proximal promoter, identified by transient transfections using apoE deletion mutants, DNAP, and chromatin immunoprecipitation assays. Overall, the dual effect of c-Jun on apoE gene expression led to decreased cholesterol efflux in macrophages resident in the atherosclerotic plaque synergized with an increased level of systemic apoE secreted by the liver to exacerbate atherogenesis. View Full-Text
Keywords: apoE; apolipoproteins; c-Jun; AP-1; promoter; enhancer; ME.2; hepatocytes; macrophages apoE; apolipoproteins; c-Jun; AP-1; promoter; enhancer; ME.2; hepatocytes; macrophages
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MDPI and ACS Style

Trusca, V.G.; Fuior, E.V.; Kardassis, D.; Simionescu, M.; Gafencu, A.V. The Opposite Effect of c-Jun Transcription Factor on Apolipoprotein E Gene Regulation in Hepatocytes and Macrophages. Int. J. Mol. Sci. 2019, 20, 1471. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061471

AMA Style

Trusca VG, Fuior EV, Kardassis D, Simionescu M, Gafencu AV. The Opposite Effect of c-Jun Transcription Factor on Apolipoprotein E Gene Regulation in Hepatocytes and Macrophages. International Journal of Molecular Sciences. 2019; 20(6):1471. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061471

Chicago/Turabian Style

Trusca, Violeta G., Elena V. Fuior, Dimitris Kardassis, Maya Simionescu, and Anca V. Gafencu 2019. "The Opposite Effect of c-Jun Transcription Factor on Apolipoprotein E Gene Regulation in Hepatocytes and Macrophages" International Journal of Molecular Sciences 20, no. 6: 1471. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061471

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