The Liver X Receptor Ligand T0901317 Down-regulates APOA5 GeneExpression through Activation of SREBP-1c
Journal Article
·
· The Journal of Biological Chemistry
Alterations in the expression of the recently discovered apolipoprotein A5 gene strongly affect plasma triglyceride levels. In this study, we investigated the contribution of APOA5 to the liver X-receptor (LXR) ligand mediated effect on plasma triglyceride levels.Following treatment with the LXR ligand T0901317, we found that APOA5mRNA levels were decreased in hepatoma cell lines. The observation that no down-regulation of APOA5 promoter activity was obtained by LXR-retinoid X receptor (RXR) co-transfection prompted us to explore the possible involvement of the known LXR target gene SREBP-1c (sterol regulatory element-binding protein 1c). In fact, we found that co-transfection with the active form of SREBP-1c down-regulated APOA5promoter activity in a dose-dependent manner. We then scanned the human APOA5 promoter sequence and identified two putative E-box elements that were able to bind specifically SREBP-1c in gel-shift assays and were shown to be functional by mutation analysis. Subsequent suppression of SREBP-1 mRNA through small interfering RNA interference abolished the decrease of APOA5 mRNA in response to T0901317. Finally, administration of T0901317 to hAPOA5 transgenic mice revealed a significant decrease OF APOA5 mRNA in liver tissue and circulating apolipoprotein AV protein in plasma, confirming that the described down-regulation also occurs in vivo. Taken together, our results demonstrate that APOA5 gene expression is regulated by the LXR ligand T0901317 in a negative manner through SREBP-1c. These findings may provide a new mechanism responsible for the elevation of plasma triglyceride levels by LXR ligands and support the development of selective LXR agonists, not affecting SREBP-1c, as beneficial modulators of lipid metabolism.
- Research Organization:
- Ernest Orlando Lawrence Berkeley NationalLaboratory, Berkeley, CA (US)
- Sponsoring Organization:
- USDOE. Office of Management Budget and Evaluation; NationalInstitutes of Health Grants HL071954A and HL66681
- DOE Contract Number:
- AC02-05CH11231
- OSTI ID:
- 859751
- Report Number(s):
- LBNL--57968; BnR: 400412000
- Journal Information:
- The Journal of Biological Chemistry, Journal Name: The Journal of Biological Chemistry Journal Issue: 44 Vol. 279
- Country of Publication:
- United States
- Language:
- English
Similar Records
Liver X receptor agonist downregulates hepatic apoM expression in vivo and in vitro
Orphan nuclear receptor Nur77 participates in human apolipoprotein A5 gene expression
Rev-erb beta regulates the Srebp-1c promoter and mRNA expression in skeletal muscle cells
Journal Article
·
Fri Jun 20 00:00:00 EDT 2008
· Biochemical and Biophysical Research Communications
·
OSTI ID:21143725
Orphan nuclear receptor Nur77 participates in human apolipoprotein A5 gene expression
Journal Article
·
Thu Jan 28 23:00:00 EST 2010
· Biochemical and Biophysical Research Communications
·
OSTI ID:22202356
Rev-erb beta regulates the Srebp-1c promoter and mRNA expression in skeletal muscle cells
Journal Article
·
Fri Oct 30 00:00:00 EDT 2009
· Biochemical and Biophysical Research Communications
·
OSTI ID:22199852