Transgenic mice expressing a human apolipoprotein[a] allele

Francesco Acquati, Robert E Hammer, Barbara Ercoli, Vincent Mooser, Tao Ruixan, Volker Rönicke, Alessandra Michalich, Giulia Chiesa, Roberto Taramelli, Helen H Hobbs, Hans Joachim Müller

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

The most important determinant of plasma levels of Lp[a] are sequence differences at the highly polymorphic apolipoprotein[a] (apo[a]) locus. To define the sequences that mediate the regulation of apo[a] expression, we cloned a 370 kb DNA fragment that included a 130 kb apo[a] gene, and 40 kb 5'- and 200 kb 3'-flanking region from an individual with high plasma levels of Lp[a] using a YAC vector. This genomic clone was used to generate transgenic mice. In the YAC-apo[a] transgenic mouse, apo[a] was only expressed in the liver, as it is in humans. The mean serum level of apo[a] in 4-week-old YAC-apo[a] transgenic mice was 20 mg/dl. In the female mice the levels of apo[a] varied over a 1.5-fold range during the 4-day estrus cycle and the levels correlated directly with serum progesterone levels. The serum levels of apo[a] decreased to almost undetectable level in male mice after puberty and this decrease was reversed by castration. Ingestion of a high- fat diet resulted in a ~100-fold fall in hepatic apo[a] mRNA levels and >60- fold decrease in serum apo[a] levels. To delimit the control elements that mediate tissue-specific and sex hormone-responsive apo[a] transcription, we derived a reporter YAC in which 40 kb of 5' flanking sequences from the cloned apo[a] allele were linked to a luciferase reporter gene. Analysis of four independent transgenic lines revealed no hepatic luciferase expression, suggesting that important cis-acting elements located outside the apo[a] 5'- flanking region are necessary for in vivo expression of apo[a].

Original languageEnglish (US)
Pages (from-to)994-1006
Number of pages13
JournalJournal of lipid research
Volume40
Issue number6
StatePublished - Jun 1999

Keywords

  • Homologous recombination
  • Yeast artificial chromosomes

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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