Regulation of the human apolipoprotein AIV gene expression in transgenic mice

The apolipoprotein (Apo) AI-CIII-AIV gene cluster has a complex pattern of gene expression that is modulated by both gene- and cluster-specific cis-ac ting elements. In particular the regulation of Apo AIV expression has been previously studied in vivo and in vitro including several transgenic moose lines but a complete, consistent picture of the tissue-specific controls is still missing. We have analysed the role of the Apo AIV 3' flanking sequen ces in the regulation of gene expression using both in vitro and in vivo sy stems including three lines of transgenic mice. The transgene consisted of a human fragment containing 7 kb of the 5' flanking region, the Apo AIV gen e itself and 6 kb of the 3' flanking region (-7+6 Apo ATV), Accurate analys is of the Apo AIV mRNA levels using quantitative PCR and Northern blots sho wed that the -7+6 kb Apo AIV fragment confers liver-specific regulation in that the human Apo AIV transgene is expressed at approximately the same lev el as the endogenous mouse Apo AIV gene. In contrast, the intestinal regula tion of the transgene did not follow the pattern observed with the endogeno us gene although it produced a much higher intestinal expression following the accepted human pattern. Therefore, this animal model provides an excell ent substrate to design therapeutic protocols for those metabolic derangeme nts that may benefit from variations in Apo AIV levels and its anti-atherog enic effect. (C) 1999 Federation of European Biochemical Societies.