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MUCOSAL BIOLOGY

Hepatocyte nuclear factor-4 mediates apolipoprotein A-IV transcriptional regulation by fatty acid in newborn swine enterocytes

Children's Foundation Research Center of Memphis at Le Bonheur Children's Medical Center, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee

Submitted 10 February 2007 ; accepted in final form 6 June 2007

Hepatocyte nuclear factor-4 (HNF-4) 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-4 in the regulation of apo A-IV gene transcription by dietary fatty acid in neonatal swine small intestine. HNF-4 mRNA was expressed in liver > intestine > kidney in suckling, weanling, and weaned pigs. Jejunal HNF-4 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-4, apo A-IV, and MTP mRNA, similar to that observed in vivo. When HNF-4 expression was driven by doxycycline by using the TET-On system in the absence of OA to observe the effect of HNF-4 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-4 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-4 that is itself induced by a lipid-mediated mechanism.

apo B; IPEC-1 cells; lipid absorption; microsomal triglyceride transfer protein; neonate; oleic acid