TY - JOUR
T1 - Transcriptional regulation of human microsomal triglyceride transfer protein by hepatocyte nuclear factor-4α
AU - Sheena, Vered
AU - Hertz, Rachel
AU - Nousbeck, Janna
AU - Berman, Ina
AU - Magenheim, Judith
AU - Bar-Tana, Jacob
PY - 2005/2
Y1 - 2005/2
N2 - Microsomal triglyceride transfer protein (MTP) catalyzes the assembly of triglyceride (TG)-rich apolipoprotein B-containing liver (e.g., VLDL) and intestinal (e.g., chylomicron) lipoproteins. The human MTP gene promoter is reported here to associate in vivo with endogenous hepatocyte nuclear factor-4α (HNF-4α) and to be transactivated or transsuppressed by overexpressed or by dominant negative HNF-4α, respectively. Human MTP (hMTP) transactivation by HNF-4α is accounted for by the concerted activity of distal (-83/-70) and proximal (-50/-38) direct repeat 1 elements of the hMTP promoter that bind HNF-4α. Transactivation by HNF-4α is specifically antagonized by chicken ovalbumin upstream promoter. Transcriptional activation of hMTP by HNF-4α is mediated by HNF-4α domains engaged in ligand binding and ligand-driven transactivation and is further complemented by HNF-4α/HNF-1α synergism that involves the HNF-4α activation function 1 (AF-1) domain. hMTP transactivation by HNF-4α is specifically inhibited by β,β-tetramethyl-hexadecanedioic acid acting as an HNF-4α antagonist ligand. hMTP transactivation by HNF-4α may account for the activation or inhibition of MTP expression and the production of TG-rich lipoproteins by agonist (e.g., saturated fatty acids) or antagonist [e.g., (n-3) PUFA, hypolipidemic fibrates, or Methyl-substituted dicarboxylic acid (Medica) compounds] HNF-4α ligands.
AB - Microsomal triglyceride transfer protein (MTP) catalyzes the assembly of triglyceride (TG)-rich apolipoprotein B-containing liver (e.g., VLDL) and intestinal (e.g., chylomicron) lipoproteins. The human MTP gene promoter is reported here to associate in vivo with endogenous hepatocyte nuclear factor-4α (HNF-4α) and to be transactivated or transsuppressed by overexpressed or by dominant negative HNF-4α, respectively. Human MTP (hMTP) transactivation by HNF-4α is accounted for by the concerted activity of distal (-83/-70) and proximal (-50/-38) direct repeat 1 elements of the hMTP promoter that bind HNF-4α. Transactivation by HNF-4α is specifically antagonized by chicken ovalbumin upstream promoter. Transcriptional activation of hMTP by HNF-4α is mediated by HNF-4α domains engaged in ligand binding and ligand-driven transactivation and is further complemented by HNF-4α/HNF-1α synergism that involves the HNF-4α activation function 1 (AF-1) domain. hMTP transactivation by HNF-4α is specifically inhibited by β,β-tetramethyl-hexadecanedioic acid acting as an HNF-4α antagonist ligand. hMTP transactivation by HNF-4α may account for the activation or inhibition of MTP expression and the production of TG-rich lipoproteins by agonist (e.g., saturated fatty acids) or antagonist [e.g., (n-3) PUFA, hypolipidemic fibrates, or Methyl-substituted dicarboxylic acid (Medica) compounds] HNF-4α ligands.
KW - Hypolipidemic drugs
KW - Lipoproteins
KW - Medica 16
KW - Nuclear receptors
UR - http://www.scopus.com/inward/record.url?scp=13944249827&partnerID=8YFLogxK
U2 - 10.1194/jlr.M400371-JLR200
DO - 10.1194/jlr.M400371-JLR200
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C2 - 15547294
AN - SCOPUS:13944249827
SN - 0022-2275
VL - 46
SP - 328
EP - 341
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 2
ER -