Regulation and activity of the human ABCA1 gene in transgenic mice

The ABCA1 transporter is one of the limiting steps in cellular cholesterol efflux, To study the expression and activity of the human ABCA1 gene in viv o we have examined mice containing two human BAC transgenes with different 5' ends. Mice containing a 255-kilobase (kb) BAC transgene, including 70 kb upstream of the previously defined exon I, demonstrated a pattern of tissu e-specific expression mimicking that of the endogenous mouse gene. Compared with macrophages from control mice, macrophages from these transgenics had increases in apoA-I cholesterol efflux heightened in response to increases in cell cholesterol content. The observed increase in macrophage apoA-I-me diated cholesterol efflux was not accompanied by alterations in plasma high density lipoprotein in the transgenics. Although mice containing a smaller 171-kb human BAC transgene, lacking the previously described exon 1 and AB CA1 promoter, did not express human ABCA1 in macrophages, they did express the human transgene in liver at levels comparable with those of the ortholo gous mouse gene. Analysis by 5' rapid amplification of cDNA ends of liver m RNA from these animals revealed a new ABCA1 exon 1 (exon 1A) and a previous ly unrecognized promoter. Analysis of human tissue revealed that exon 1A co ntaining transcripts accounted for a high proportion of the ABCA1 mRNAs pre sent in human liver, This analysis of ABCA1 transgenics showed that the exp ression of human ABCA1 transgenes can result in increased cholesterol efflu x from macrophages, unaccompanied by changes in plasma high density lipopro tein, and identified a new ABCA1 promoter in humans.