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.
Vu-Dac
N
N
U.325 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France.
Gervois
P
P
Torra
I P
IP
Fruchart
J C
JC
Kosykh
V
V
Kooistra
T
T
Princen
H M
HM
Dallongeville
J
J
Staels
B
B
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