FTF and LRH-1, two related but different transcription factors in human Caco-2 cells: their different roles in the regulation of bile acid transport.
The apical sodium dependent bile acid transporter (ASBT) mediates ileal bile acid reabsorption. The transcription factors, liver receptor homologue-1 (LRH-1:mouse) and fetoprotein transcription factor (FTF:human), are presumably orthologues. Bile-acid induced negative feedback regulation of mouse (m) and human (h) ASBT occurs via LRH-1 and RAR/RXR, respectively. hASBT has a potential FTF cis-element, although its functional role is unknown. hASBT and mASBT promoter constructs and an FTF cis-element mutated hASBT (hASBT/FTFmu) were assessed in human Caco-2 cells treated with chenodeoxycholic acid (CDCA) and/or co-transfected with hFTF, mLRH-1, or specific small interfering FTF or LRH-1 RNA (siFTF or siLRH). Basal promoter activity was reduced in hASBT/FTFmu, although bile acid response persisted. hFTF activated hASBT but not mASBT, while mLRH-1 activated mASBT but not hASBT. siFTF reduced hASBT but not mASBT activity; siLRH reduced mASBT but not hASBT activity. siLRH but not siFTF abrogated bile acid responsiveness. Electrophoretic mobility shift assays demonstrated distinct and specific binding of the mLRH-1 or hFTF cis-elements. In conclusion, FTF and LRH-1 are two related but different transcription factors in human Caco-2 cells, suggesting that they may be homologues and not orthologues. FTF is not involved directly in bile acid mediated negative feedback regulation of the ASBT.
Department of Pediatrics, Division of Pediatric Hepatology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1656, New York, NY 10029, USA.
Debra H
DH
Pan
Frank
F
Chen
Ezequiel
E
Neimark
Xiaoping
X
Li
Benjamin L
BL
Shneider
D000595:Amino Acid Sequence; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport; D015152:Blotting, Northern; D015153:Blotting, Western; D018938:Caco-2 Cells; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050436:Regulatory Elements, Transcriptional / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D027981:Symporters / Q000235:genetics; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; C431936:Nr5a2 protein, mouse; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; D014157:Transcription Factors; C099948:fetoprotein transcription factor; C071908:sodium-bile acid cotransporter; D004247:DNA