Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids.
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.
U.325 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France.
N
N
Vu-Dac
P
P
Gervois
I P
IP
Torra
J C
JC
Fruchart
V
V
Kosykh
T
T
Kooistra
H M
HM
Princen
J
J
Dallongeville
B
B
Staels
D000328:Adult; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000096:biosynthesis* / Q000235:genetics; D001565:Benzoates / Q000494:pharmacology; D000077610:Bexarotene; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D019281:Dimerization; D004311:Double-Blind Method; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015228:Hypertriglyceridemia / Q000139:chemically induced*; D015474:Isotretinoin / Q000009:adverse effects / Q000494:pharmacology*; D008099:Liver / Q000166:cytology; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D001565:Benzoates; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; D000077610:Bexarotene; D015474:Isotretinoin