Human ABCA1 BAC transgenic mice show increased high density lipoprotein cholesterol and apoAI-dependent efflux stimulated by an internal promoter containing liver X receptor response elements in intron 1

By using BAC transgenic mice, we have shown that increased human ABCA1 prot ein expression results in a significant increase in cholesterol efflux in d ifferent tissues and marked elevation in high density lipoprotein (HDL)-cho lesterol levels associated with increases in apoAI and apoAII. Three novel ABCA1 transcripts containing three different transcription initiation sites that utilize sequences in intron I have been identified. In BAC transgenic mice there is an increased expression of ABCA1 protein, but the distributi on of the ABCA1 product in different cells remains similar to wild type mic e. An internal promoter in human intron I containing liver X response eleme nts is functional in vivo and directly contributes to regulation of the hum an ABCA1 gene in multiple tissues and to raised HDL cholesterol, apoAI, and apoAII levels. A highly significant relationship between raised protein le vels, increased efflux, and level of HDL elevation is evident. These data p rovide proof of the principle that increased human ABCA1 efflux activity is associated with an increase in HDL levels in vivo.