title: Hepatocyte nuclear factor-4 mediates apolipoprotein A-IV transcriptional regulation by fatty acid in newborn swine enterocytes.
abstract: Hepatocyte nuclear factor-4alpha (HNF-4alpha) regulates transcription of several genes involved in lipid metabolism, including that of apolipoprotein (apo) A-IV, which is tightly regulated by lipid absorption and enhances enterocyte chylomicron secretion. Studies were performed to define the role of HNF-4alpha in the regulation of apo A-IV gene transcription by dietary fatty acid in neonatal swine small intestine. HNF-4alpha mRNA was expressed in liver > intestine > kidney in suckling, weanling, and weaned pigs. Jejunal HNF-4alpha mRNA and protein and apo A-IV and swine microsomal triglyceride transfer protein (MTP) large subunit mRNA expression were induced in parallel in 2-day-old swine by a 24-h high-fat intraduodenal infusion. In IPEC-1 cells, incubation with oleic acid (OA) resulted in coordinate induction of both HNF-4alpha, apo A-IV, and MTP mRNA, similar to that observed in vivo. When HNF-4alpha expression was driven by doxycycline by using the TET-On system in the absence of OA to observe the effect of HNF-4alpha directly on apo A-IV and MTP mRNA levels in the absence of other factors that might be concomitantly induced by fatty acid absorption, apo A-IV and MTP expression were increased. In luciferase reporter gene assays in IPEC-1 cells using apo A-IV/C-III intergenic region constructs, TET-On-regulated HNF-4alpha expression without OA increased luciferase activity, and incubation with OA did not further increase activity. These data suggest that acute induction of the apo A-IV and MTP genes by dietary lipid in newborn intestine occurs, at least in part, via ligand-independent transactivation by HNF-4alpha that is itself induced by a lipid-mediated mechanism.
authors.affiliation: Children's Foundation Research Center of Memphis, Le Bonheur Children's Medical Center, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
authors.forename: Shuangying
authors.initials: S
authors.lastname: Leng
authors.forename: Song
authors.initials: S
authors.lastname: Lu
authors.forename: Ying
authors.initials: Y
authors.lastname: Yao
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Kan
authors.forename: Gabriel S
authors.initials: GS
authors.lastname: Morris
authors.forename: Brad R
authors.initials: BR
authors.lastname: Stair
authors.forename: Mathew A
authors.initials: MA
authors.lastname: Cherny
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Black
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001054:Apolipoproteins A / Q000096:biosynthesis* / Q000235:genetics; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D002914:Chylomicrons / Q000378:metabolism; D021901:DNA, Intergenic; D004041:Dietary Fats / Q000008:administration & dosage / Q000378:metabolism; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D017930:Genes, Reporter; D051557:Hepatocyte Nuclear Factor 4 / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D007583:Jejunum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008156:Luciferases; D008969:Molecular Sequence Data; D019301:Oleic Acid / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D034421:Sus scrofa; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation
chemical_list: D001054:Apolipoproteins A; D002352:Carrier Proteins; D002914:Chylomicrons; D021901:DNA, Intergenic; D004041:Dietary Fats; D051557:Hepatocyte Nuclear Factor 4; D012333:RNA, Messenger; C022205:apolipoprotein A-IV; C106092:microsomal triglyceride transfer protein; D019301:Oleic Acid; D008156:Luciferases