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

J. Biol. Chem., Vol. 278, Issue 33, 30478-30486, August 15, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/33/30478    most recent M304201200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kang, S. Articles by Davis, R. A. Search for Related Content PubMed PubMed Citation Articles by Kang, S. Articles by Davis, R. A. Social Bookmarking                      What's this?

ARP-1/COUP-TF II Determines Hepatoma Phenotype by Acting as Both a Transcriptional Repressor of Microsomal Triglyceride Transfer Protein and an Inducer of CYP7A1^*

Sohye Kang, Nathanael J. Spann, To Y. Hui and Roger A. Davis 

From the Mammalian Cell and Molecular Biology Laboratory, Department of Biology, Molecular Biology Institute and Heart Institute, San Diego State University, San Diego, California 92182-4614

L35 and FAO cells were derived as single cell isolates from H35 cells. Whereas L35 cells do not express microsomal triglyceride transfer protein (MTP), which regulates lipoprotein secretion, they express CYP7A1, which regulates bile acid synthesis from cholesterol. FAO cells display the opposite phenotype (i.e. expression of MTP but not CYP7A1). We examined the molecular basis of the transcriptional inactivation of the MTP gene in L35 cells. Nested deletion and mutagenesis studies show that a conserved DR1 element within the 135-bp proximal MTP promoter is responsible for differential expression by L35 and FAO cells. Yeast one-hybrid screening identified apolipoprotein A1 regulatory protein-1/chicken ovalbumin upstream promoter transcription factor II (ARP-1/COUP-TFII) and retinoid X receptor (RXR) as the protein factors that can bind to the conserved DR1 element. Nuclear extracts from L35 cells contained 2-fold more ARP-1/COUP-TFII and 50% less RXR than those from FAO cells. Immunologic studies show that in L35 cells, ARP-1/COUP-TFII is bound to the DR1 element, whereas in FAO cells, a complex containing RXR is bound to the DR1 element. Co-transfection studies show that ARP-1/COUP-TFII repressed MTP promoter activity by 70% in FAO hepatoma cells, whereas RXR and its ligand 9-cis-retinoic acid increased MTP promoter activity by 6-fold in L35 cells. The combined data suggest that in the context of the MTP promoter, ARP-1/COUP-TFII (repressor) and a complex containing RXR (inducer) compete for the DR1 element. Analysis of the CYP7A1 promoter revealed that it is 5-fold more active in L35 cells than in FAO cells. Co-transfection of an ARP-1/COUP-TFII expression vector showed that it enhances CYP7A1 promoter activity by 6-fold in FAO cells. These combined findings indicate that ARP-1/COUP-TFII acts as both a transcriptional repressor (of MTP) and as a transcription activator (of CYP7A1). This dual function of ARP-1/COUP-TFII may play an important role in determining the metabolic phenotype of individual liver cells.

Received for publication, April 22, 2003 , and in revised form, May 29, 2003.

^* This work was supported by National Institutes of Health Grant HL51648. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Biology, Life Sciences Bldg. LS307, 5500 Campanile Dr., San Diego State University, San Diego, CA 92182-4614. Tel.: 619-594-7936; Fax: 619-594-7937; E-mail: rdavis{at}SUNSTROKE.sdsu.edu.

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

This article has been cited by other articles:

				G. Benoit, A. Cooney, V. Giguere, H. Ingraham, M. Lazar, G. Muscat, T. Perlmann, J.-P. Renaud, J. Schwabe, F. Sladek, et al. International Union of Pharmacology. LXVI. Orphan Nuclear Receptors Pharmacol. Rev., December 1, 2006; 58(4): 798 - 836. [Abstract] [Full Text] [PDF]

				N. J. Spann, S. Kang, A. C. Li, A. Z. Chen, E. P. Newberry, N. O. Davidson, S. T. Y. Hui, and R. A. Davis Coordinate Transcriptional Repression of Liver Fatty Acid-binding Protein and Microsomal Triglyceride Transfer Protein Blocks Hepatic Very Low Density Lipoprotein Secretion without Hepatosteatosis J. Biol. Chem., November 3, 2006; 281(44): 33066 - 33077. [Abstract] [Full Text] [PDF]

				A. M. Domitrovich, D. J. Felmlee, and A. Siddiqui Hepatitis C Virus Nonstructural Proteins Inhibit Apolipoprotein B100 Secretion J. Biol. Chem., December 2, 2005; 280(48): 39802 - 39808. [Abstract] [Full Text] [PDF]

				V. Sheena, R. Hertz, J. Nousbeck, I. Berman, J. Magenheim, and J. Bar-Tana Transcriptional regulation of human microsomal triglyceride transfer protein by hepatocyte nuclear factor-4{alpha} J. Lipid Res., February 1, 2005; 46(2): 328 - 341. [Abstract] [Full Text] [PDF]

				C. Ameen, U. Edvardsson, A. Ljungberg, L. Asp, P. Akerblad, A. Tuneld, S.-O. Olofsson, D. Linden, and J. Oscarsson Activation of Peroxisome Proliferator-activated Receptor {alpha} Increases the Expression and Activity of Microsomal Triglyceride Transfer Protein in the Liver J. Biol. Chem., January 14, 2005; 280(2): 1224 - 1229. [Abstract] [Full Text] [PDF]

				H. Hirokane, M. Nakahara, S. Tachibana, M. Shimizu, and R. Sato Bile Acid Reduces the Secretion of Very Low Density Lipoprotein by Repressing Microsomal Triglyceride Transfer Protein Gene Expression Mediated by Hepatocyte Nuclear Factor-4 J. Biol. Chem., October 29, 2004; 279(44): 45685 - 45692. [Abstract] [Full Text] [PDF]