HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: M400371-JLR200v1 46/2/328    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sheena, V. Articles by Bar-Tana, J. Search for Related Content PubMed PubMed Citation Articles by Sheena, V. Articles by Bar-Tana, J. Social Bookmarking                      What's this?

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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				W.-S. Au, L. Lu, C.-M. Yeung, C.-C. Liu, O. G Wong, L. Lai, H.-f. Kung, and M. C Lin Hepatocyte nuclear factor 1 binding element within the promoter of microsomal triglyceride transfer protein (MTTP) gene is crucial for MTTP basal expression and insulin responsiveness J. Mol. Endocrinol., October 1, 2008; 41(4): 229 - 238. [Abstract] [Full Text] [PDF]

				M. H. Black, T. E. Fingerlin, H. Allayee, W. Zhang, A. H. Xiang, E. Trigo, J. Hartiala, A. B. Lehtinen, S. M. Haffner, R. N. Bergman, et al. Evidence of Interaction Between PPARG2 and HNF4A Contributing to Variation in Insulin Sensitivity in Mexican Americans Diabetes, April 1, 2008; 57(4): 1048 - 1056. [Abstract] [Full Text] [PDF]

				X. Pan and M. M. Hussain Diurnal Regulation of Microsomal Triglyceride Transfer Protein and Plasma Lipid Levels J. Biol. Chem., August 24, 2007; 282(34): 24707 - 24719. [Abstract] [Full Text] [PDF]

				S. Leng, S. Lu, Y. Yao, Z. Kan, G. S. Morris, B. R. Stair, M. A. Cherny, and D. D. Black Hepatocyte nuclear factor-4 mediates apolipoprotein A-IV transcriptional regulation by fatty acid in newborn swine enterocytes Am J Physiol Gastrointest Liver Physiol, August 1, 2007; 293(2): G475 - G483. [Abstract] [Full Text] [PDF]

				S. K. Dougan, P. Rava, M. M. Hussain, and R. S. Blumberg MTP regulated by an alternate promoter is essential for NKT cell development J. Exp. Med., March 19, 2007; 204(3): 533 - 545. [Abstract] [Full Text] [PDF]

				L. O. Li, D. G. Mashek, J. An, S. D. Doughman, C. B. Newgard, and R. A. Coleman Overexpression of Rat Long Chain Acyl-CoA Synthetase 1 Alters Fatty Acid Metabolism in Rat Primary Hepatocytes J. Biol. Chem., December 1, 2006; 281(48): 37246 - 37255. [Abstract] [Full Text] [PDF]

				L. E. Rufibach, S. A. Duncan, M. Battle, and S. S. Deeb Transcriptional regulation of the human hepatic lipase (LIPC) gene promoter J. Lipid Res., July 1, 2006; 47(7): 1463 - 1477. [Abstract] [Full Text] [PDF]

				C. W. Rowley, L. J. Staloch, J. K. Divine, S. P. McCaul, and T. C. Simon Mechanisms of mutual functional interactions between HNF-4{alpha} and HNF-1{alpha} revealed by mutations that cause maturity onset diabetes of the young Am J Physiol Gastrointest Liver Physiol, March 1, 2006; 290(3): G466 - G475. [Abstract] [Full Text] [PDF]