The authors have no conflicts of interest to declare.
Inhibition of Apolipoprotein A-I Expression by TNF-Alpha in HepG2 Cells: Requirement for c-jun
Article first published online: 13 DEC 2013
© 2013 Wiley Periodicals, Inc.
Journal of Cellular Biochemistry
Volume 115, Issue 2, pages 253–260, February 2014
How to Cite
Parseghian, S., Onstead-Haas, L. M., Wong, N. C.W., Mooradian, A. D. and Haas, M. J. (2014), Inhibition of Apolipoprotein A-I Expression by TNF-Alpha in HepG2 Cells: Requirement for c-jun. J. Cell. Biochem., 115: 253–260. doi: 10.1002/jcb.24656
- Issue published online: 13 DEC 2013
- Article first published online: 13 DEC 2013
- Accepted manuscript online: 22 AUG 2013 07:26AM EST
- Manuscript Accepted: 14 AUG 2013
- Manuscript Received: 19 JUN 2013
- Dean's Research Fund
- PRO-INFLAMMATORY CYTOKINES;
- APOLIPOPROTEIN A-I;
- HIGH-DENSITY LIPOPROTEIN-CHOLESTEROL;
- TRANSCRIPTIONAL REGULATION;
- CARDIOVASCULAR DISEASE
Tumor necrosis factor alpha (TNF α) signals in part through the mitogen activated protein (MAP) kinase c-jun-N-terminal kinase (JNK). Activation of JNK has been shown to promote insulin resistance and dyslipidemia, including reductions in plasma high-density lipoprotein (HDL) and apolipoprotein A-I (apo A-I). To examine how TNF α-mediated JNK activation inhibits hepatic apo A-I production, the effects of c-jun activation on apo A-I gene expression were examined in HepG2 cells. Apo A-I gene expression and promoter activity were measured by Northern and Western blotting and transient transfection. Transient transfection and siRNA were used to specifically over-express or knockout c-jun, c-jun-N-terminal kinase-1 and -2 (JNK1 and JNK2, respectively) and mitogen-activated protein kinase-4 (MKK4). TNF α-treatment of HepG2 cells induced rapid phosphorylation of c-jun on serine 63. In cells treated with phorbol-12-myristate-13-acetate (PMA), apo A-I gene promoter activity was inhibited and apo A-I mRNA content and apo A-I protein secretion decreased. Likewise, over-expression of JNK1 and JNK2 inhibited apo A-I promoter activity. Over-expression of constitutively active MKK4, an upstream protein kinase that directly activates JNK, also inhibited apo A-I promoter activity, while over-expression of a dominant-negative MKK4 de-repressed apo A-I promoter activity in TNF α-treated cells. Inhibition of c-jun synthesis using siRNA but not a control siRNA prevented TNF α-mediated inhibition of apo A-I. These results suggest that the MKK4/JNK/c-jun signaling pathway mediates TNF α-dependent inhibition of apo A-I synthesis. J. Cell. Biochem. 115: 253–260, 2014. © 2013 Wiley Periodicals, Inc.