Synergism between nuclear receptors bound to specific hormone response elements of the hepatic control region-1 and the proximal apolipoprotein C-II promoter mediate apolipoprotein C-II gene regulation by bile acids and retinoids.
We have shown previously that the hepatic control region 1 (HCR-1) enhances the activity of the human apolipoprotein C-II (apoC-II) promoter in HepG2 cells via two hormone response elements (HREs) present in the apoC-II promoter. In the present paper, we report that the HCR-1 selectively mediates the transactivation of the apoC-II promoter by chenodeoxycholic acid (CDCA) and 9- cis -retinoic acid. CDCA, which is a natural ligand of farnesoid X receptor alpha (FXRalpha), increases the steady-state apoC-II mRNA levels in HepG2 cells. This increase in transcription requires the binding of retinoid X receptor alpha (RXRalpha)-FXRalpha heterodimers to a novel inverted repeat with one nucleotide spacing (IR-1) present in the HCR-1. This element also binds hepatocyte nuclear factor 4 and apoA-I regulatory protein-1. Transactivation of the HCR-1/apoC-II promoter cluster by RXRalpha-FXRalpha heterodimers in the presence of CDCA was abolished by mutations either in the IR-1 HRE of the HCR-1 or in the thyroid HRE of the proximal apoC-II promoter, which binds RXRalpha-thyroid hormone receptor beta (T3Rbeta) heterodimers. The same mutations also abolished transactivation of the HCR-1/apoC-II promoter cluster by RXRalpha-T3Rbeta heterodimers in the presence of tri-iodothyronine. The findings establish synergism between nuclear receptors bound to specific HREs of the proximal apoC-II promoter and the HCR-1, and suggest that this synergism mediates the induction of the HCR-1/apoC-II promoter cluster by bile acids and retinoids.
Kardassis
Dimitris
D
Department of Basic Sciences, School of Health Sciences, Faculty of Medicine, University of Crete, PO Box 1393, 71500 Heraklion, Greece. kardasis@imbb.forth.gr
Roussou
Anastasia
A
Papakosta
Paraskevi
P
Boulias
Konstantinos
K
Talianidis
Iannis
I
Zannis
Vassilis I
VI
D000077556:Alitretinoin; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C / Q000235:genetics* / Q000378:metabolism; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015153:Blotting, Western; D019556:COS Cells; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D002522:Chlorocebus aethiops; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins; D019281:Dimerization; D004357:Drug Synergism; D024202:Electrophoretic Mobility Shift Assay; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D008113:Liver Neoplasms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010957:Plasmids; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D012045:Regulatory Sequences, Nucleic Acid; D047488:Retinoid X Receptors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005765:Gastrointestinal Agents; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D047488:Retinoid X Receptors; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D002635:Chenodeoxycholic Acid; D000077556:Alitretinoin; D014212:Tretinoin; D008156:Luciferases; D015500:Chloramphenicol O-Acetyltransferase