Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids. (original) (raw)

Research Article Free access | 10.1172/JCI1581

P Gervois, I P Torra, J C Fruchart, V Kosykh, T Kooistra, H M Princen, J Dallongeville, and B Staels

U.325 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France.

Find articles by Vu-Dac, N. in:JCI |PubMed |Google Scholar

U.325 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France.

Find articles by Gervois, P. in:JCI |PubMed |Google Scholar

U.325 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France.

Find articles by Torra, I. in:[JCI](/search/results?q=author.first%5Fname%3A%22I P%22+author.last%5Fname%3A%22Torra%22&search%5Ftype=advanced) |PubMed |Google Scholar

U.325 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France.

Find articles by Fruchart, J. in:[JCI](/search/results?q=author.first%5Fname%3A%22J C%22+author.last%5Fname%3A%22Fruchart%22&search%5Ftype=advanced) |PubMed |Google Scholar

U.325 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France.

Find articles by Kosykh, V. in:JCI |PubMed |Google Scholar

U.325 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France.

Find articles by Kooistra, T. in:JCI |PubMed |Google Scholar

U.325 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France.

Find articles by Princen, H. in:[JCI](/search/results?q=author.first%5Fname%3A%22H M%22+author.last%5Fname%3A%22Princen%22&search%5Ftype=advanced) |PubMed |Google Scholar

U.325 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France.

Find articles by Dallongeville, J. in:JCI |PubMed |Google Scholar

U.325 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France.

Find articles by Staels, B. in:JCI |PubMed |Google Scholar

Published August 1, 1998 -More info

Published August 1, 1998 -Version history

View PDF

Abstract

Hypertriglyceridemia is a metabolic complication of retinoid therapy. In this study, we analyzed whether retinoids increase the expression of apo C-III, an antagonist of plasma triglyceride catabolism. In men, isotretinoin treatment (80 mg/d; 5 d) resulted in elevated plasma apo C-III, but not apo E concentrations. In human hepatoma HepG2 cells, retinoids increased apo C-III mRNA and protein production. Transient transfection experiments indicated that retinoids increase apo C-III expression at the transcriptional level. This increased apo C-III transcription is mediated by the retinoid X receptor (RXR), since LG1069 (4-[1-(5,6,7,8-tetrahydro-3,5,5,8, 8-pentamethyl-2-naphtalenyl)ethenyl]benzoic acid), a RXR-specific agonist, but not TTNPB ((E)- 4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphtalenyl)propenyl]benzoic acid), a retinoic acid receptor (RAR)-specific agonist, induced apo C-III mRNA in HepG2 cells and primary human hepatocytes. Mutagenesis experiments localized the retinoid responsiveness to a cis-element consisting of two imperfect AGGTCA sequences spaced by one oligonucleotide (DR-1), within the previously identified C3P footprint site. Cotransfection assays showed that RXR, but not RAR, activates apo C-III transcription through this element either as a homo- or as a heterodimer with the peroxisome proliferator-activated receptor. Thus, apo C-III is a target gene for retinoids acting via RXR. Increased apo C-III expression may contribute to the hypertriglyceridemia and atherogenic lipoprotein profile observed after retinoid therapy.

Version history