Inhibitory effect of the small heterodimer partner on hepatocyte nuclear factor-4 mediates bile acid-induced repression of the human angiotensinogen gene.
Bile acids function as transcriptional regulators for the genes important in bile acid synthesis and cholesterol homeostasis. In this study, we identified angiotensinogen (ANG), the precursor of vasoactive octapeptide angiotensin II, as a novel target gene of bile acids. In human ANG transgenic mice, administration of cholic acid resulted in the down-regulation of human ANG gene expression in the liver. ANG gene expression in HepG2 cells was also repressed by chenodeoxycholic acid. Because the expression of small heterodimer partner (SHP) mRNA was induced by chenodeoxycholic acid in HepG2 cells, we analyzed the effects of SHP on the human ANG promoter. Promoter mutation analysis demonstrated that SHP repressed human ANG promoter activity through the element, which has been previously determined as a binding site for hepatocyte nuclear factor-4 (HNF-4). SHP repressed human ANG promoter activity only when the HNF-4 expression vector was cotransfected in HeLa cells. Furthermore, we found that SHP bound to the HNF-4 N-terminal region including the DNA-binding domain and activation function-1 and that SHP prevented HNF-4 from binding to the human ANG promoter. These results suggest that bile acids negatively regulate the human ANG gene through the inhibitory effect of SHP on HNF-4.
Shimamoto
Yoko
Y
Center for Tsukuba Advanced Research Alliance, Aspect of Functional Genomic Biology, Institute of Applied Biochemistry, University of Tsukuba, Ten-noudai 1-1-1, Tsukuba, Ibaraki 305-8577, Japan.
Ishida
Junji
J
Yamagata
Kazuyuki
K
Saito
Tomoko
T
Kato
Hideki
H
Matsuoka
Toshiki
T
Hirota
Keiko
K
Daitoku
Hiroaki
H
Nangaku
Masaomi
M
Yamagata
Kazuya
K
Fujii
Hiroshi
H
Takeda
Jun
J
Fukamizu
Akiyoshi
A
D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001647:Bile Acids and Salts / Q000494:pharmacology*; D001665:Binding Sites; D006528:Carcinoma, Hepatocellular; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D019826:Cholic Acid / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D008099:Liver / Q000737:chemistry; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016296:Mutagenesis; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C501970:Tcfl4 protein, mouse; D014157:Transcription Factors; C099713:nuclear receptor subfamily 0, group B, member 2; D002635:Chenodeoxycholic Acid; D000808:Angiotensinogen; D004247:DNA; D008156:Luciferases; D019826:Cholic Acid