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Journal of Lipid Research, Vol. 46, 328-341, February 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Transcriptional regulation of human microsomal triglyceride transfer protein by hepatocyte nuclear factor-4

Vered Sheena, Rachel Hertz, Janna Nousbeck, Ina Berman, Judith Magenheim and Jacob Bar-Tana¹

Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120

¹ To whom correspondence should be addressed. e-mail: bartanaj{at}cc.huji.ac.il

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-4 (HNF-4) and to be transactivated or transsuppressed by overexpressed or by dominant negative HNF-4, respectively. Human MTP (hMTP) transactivation by HNF-4 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-4. Transactivation by HNF-4 is specifically antagonized by chicken ovalbumin upstream promoter. Transcriptional activation of hMTP by HNF-4 is mediated by HNF-4 domains engaged in ligand binding and ligand-driven transactivation and is further complemented by HNF-4/HNF-1 synergism that involves the HNF-4 activation function 1 (AF-1) domain. hMTP transactivation by HNF-4 is specifically inhibited by ß,ß-tetramethyl-hexadecanedioic acid acting as an HNF-4 antagonist ligand.

hMTP transactivation by HNF-4 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-4 ligands.

Abbreviations: AF-1, activation function 1; AP-1, activator protein 1; apoB, apolipoprotein B; CHIP, chromatin immunoprecipitation; CI-DICA, ,'-tetrachloro-tetradecanedioic acid; COUP-TF, chicken ovalbumin upstream promoter transcription factor; D-DR1, distal direct repeat 1; D-mut, mutated distal direct repeat 1; DR1, direct repeat 1; GFP, green fluorescent protein; hMTP, human microsomal triglyceride transfer protein; HNF-1, hepatocyte nuclear factor-1; HNF-4, hepatocyte nuclear factor-4; Medica 16, ß,ß-tetramethyl-hexadecanedioic acid; MTP, microsomal triglyceride transfer protein; P-DR1, proximal direct repeat 1; P-mut, mutated proximal direct repeat 1; PPAR, peroxisome proliferator-activated receptor ; PUFA, polyunsaturated fatty acid; RXR, retinoid X receptor; SREBP, sterol regulatory element binding protein; TG, triglyceride

Supplementary key words lipoproteins • nuclear receptors • hypolipidemic drugs • Medica 16

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