Transcriptional regulation of human microsomal triglyceride transfer protein by hepatocyte nuclear factor-4alpha.
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-4alpha (HNF-4alpha) and to be transactivated or transsuppressed by overexpressed or by dominant negative HNF-4alpha, respectively. Human MTP (hMTP) transactivation by HNF-4alpha 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-4alpha. Transactivation by HNF-4alpha is specifically antagonized by chicken ovalbumin upstream promoter. Transcriptional activation of hMTP by HNF-4alpha is mediated by HNF-4alpha domains engaged in ligand binding and ligand-driven transactivation and is further complemented by HNF-4alpha/HNF-1alpha synergism that involves the HNF-4alpha activation function 1 (AF-1) domain. hMTP transactivation by HNF-4alpha is specifically inhibited by beta,beta-tetramethyl-hexadecanedioic acid acting as an HNF-4alpha antagonist ligand. hMTP transactivation by HNF-4alpha 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-4alpha ligands.
Sheena
Vered
V
Department of Human Nutrition and Metabolism, Hebrew University Medical School, Jerusalem, Israel 91120.
Hertz
Rachel
R
Nousbeck
Janna
J
Berman
Ina
I
Magenheim
Judith
J
Bar-Tana
Jacob
J
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics*; D002384:Catalysis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002645:Chickens; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D051557:Hepatocyte Nuclear Factor 4; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D010047:Ovalbumin / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism / Q000502:physiology*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005227:Fatty Acids; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D008024:Ligands; D008079:Lipoproteins, VLDL; D010750:Phosphoproteins; D012333:RNA, Messenger; D014157:Transcription Factors; C106092:microsomal triglyceride transfer protein; D010047:Ovalbumin