Abstract
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.
Highlights
Microsomal triglyceride transfer protein (MTP) catalyzes the assembly of triglyceride (TG)-rich apolipoprotein B-containing liver (e.g., VLDL) and intestinal lipoproteins
Ad-HNF-4␣ infection resulted in 60% and 70% increases in human apoA-I and MTP mRNA levels, respectively (Fig. 1), indicating that expression of the endogenous Human MTP (hMTP) gene was modulated by added HNF-4␣
Transactivation of the hMTP gene promoter by HNF-4␣ was evaluated in HepG2 cells transfected with a CAT reporter plasmid promoted by the 5Ј-flanking Ϫ611 bp sequence of the hMTP gene promoter [(Ϫ611/ϩ87)hMTPCAT]
Summary
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. Ad-HNF-4␣ infection resulted in 60% and 70% increases in human apoA-I and MTP mRNA levels, respectively (Fig. 1), indicating that expression of the endogenous hMTP gene was modulated by added HNF-4␣.
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