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M404255200v1
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Papers In Press, published online ahead of print August 26, 2004
J. Biol. Chem, 10.1074/jbc.M404255200
Submitted on April 16, 2004
Revised on August 26, 2004
Accepted on August 26, 2004

Bile acid reduces the secretion of very low density lipoprotein by repressing microsomal triglyceride transfer protein gene expression mediated by hepatocyte nuclear factor-4

Hisako Hirokane, Mayuko Nakahara, Shizuko Tachibana, Makoto Shimizu, and Ryuichiro Sato

Department of Applied Biological Chemistry, University of Tokyo, Tokyo, Tokyo 113-8657

Corresponding Author: aroysato{at}mail.ecc.u-tokyo.ac.jp

Microsomal triglyceride transfer protein (MTP) is involved in the transfer of triglycerides, cholesterol esters and phospholipids to newly synthesized apolipoprotein (apo) B. It is therefore essential for lipoprotein synthesis and secretion in the liver and the small intestine. Although several recent experiments have revealed the transcriptional regulation of the MTP gene, little has been revealed to date about hepatocyte nuclear factor 4 (HNF-4)-dependent regulation. We here report that the human MTP gene promoter contains a pair of functional responsive elements for HNF-4 and HNF-1, the latter of which is another target gene of HNF-4. Chromatin immunoprecipitation assays provide evidence that endogenous HNF-4 and HNF-1 can bind these elements in chromatin. In Hep G2 cells overexpression of either a dominant negative form of HNF-4 or siRNAs against HNF-4 dramatically reduces the activities of both the wild type and the HNF-4 site mutant MTP promoter. This suggests HNF-4 regulates MTP gene expression, either directly, or indirectly through elevated HNF-1 levels. When Hep G2 cells were cultured with chenodeoxycholic acid (CDCA), a ligand for the farnesoid x receptor (FXR), mRNA levels for MTP and apo B were reduced due to increased expression of the factor small heterodimer partner (SHP), which factor suppresses HNF-4 activities. CDCA, but not a synthetic FXR ligand, attenuated expression of HNF-4, bringing about a further suppression of MTP gene expression. Over time the intracellular MTP protein levels and apo B secretion in the culture medium significantly declined. These results indicate that two nuclear receptors, HNF-4 and FXR, are closely involved in MTP gene expression, and provide evidence for a novel interaction between bile acids and lipoprotein metabolism.


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