The human β-globin LCR and promoter can confer tissue-specific expression of a human CETP cDNA in transgenic rats

Two transgenic founder rats (CETP2 and CETP4) expressing the human cholesteryl ester transfer protein (hCETP) were produced by the microinjection of single-cell rat embryos with a linear fragment encompassing a hCETP cDNA regulated by the human beta-globin promoter and locus control region (LCR). Northern blot analysis of RNA isolated from the transgenic offspring of CETP4 determined that hCETP was being expressed appropriately from the human beta-globin regulatory sequences. CETP transcripts were detected in the bone marrow, blood and spleens of adult animals, and in the livers of foetal animals. a result consistent with the role in erythropoiesis played by these tissues. Although developmentally-regulated expression of the transgene mimicked that of endogenous beta-globin, stage-specific quantitative differences were noted. While circulating levels of hCETP in the plasma from the CETP4 lineage were approximately 10-fold less than that observed in human subjects, the expression levels were consistent both between and within generations. In addition, the second founder animal. CETP2, while not transmitting the transgene to its progeny, did display tissue-specific expression similar to that found for the CETP4 lineage. Analysis of the plasma levels of various lipids in experimental groups of transgenic and control rats, fed either a high fat, high cholesterol diet or a standard chow diet, revealed that hCETP expression had a significant influence on phospholipid, triglyceride, total cholesterol and free cholesterol plasma levels. These results emphasise the value of the human beta-globin LCR for the establishment of trans genic lineages exhibiting stable, reproducible profiles of secreted proteins.