The liver X receptor ligand T0901317 down-regulates APOA5 gene expression through activation of SREBP-1c.
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 APOA5 mRNA 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 APOA5 promoter 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.
Département d'Athérosclérose, UR545 INSERM, Institut Pasteur de Lille and Faculté de Pharmacie de Lille, 1 rue du Pr. Calmette BP 245, 59019 Lille Cedex, France, Genfit SA, Loos F-59120, France.
Heidelinde
H
Jakel
Maxime
M
Nowak
Emanuelle
E
Moitrot
Hélène
H
Dehondt
Dean W
DW
Hum
Len A
LA
Pennacchio
Jamila
J
Fruchart-Najib
Jean-Charles
JC
Fruchart
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins / Q000032:analysis / Q000235:genetics*; D001054:Apolipoproteins A; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D020218:Response Elements / Q000502:physiology; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D014157:Transcription Factors / Q000502:physiology*; D014162:Transfection; D014280:Triglycerides / Q000097:blood; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000924:Anticholesteremic Agents; D000072040:Apolipoprotein A-V; D001053:Apolipoproteins; D001054:Apolipoproteins A; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D014157:Transcription Factors; D014280:Triglycerides; C437704:APOA5 protein, human; C499058:Apoa5 protein, mouse; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides