Abstract
The plasma cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl ester from high density lipoprotein to other lipoproteins. The human DETP gene produces two forms of mRNA, with or without exon 9 (E9)-derived sequences. To study the function and regulation of alternative splicing the CETP gene, transgenic mice were prepared 1) with the metallothionein (mT) promoter driving an E9-deleted construct (mT.CETP(-E9) transgene), and 2) with the natural flanking regions (NFR) controlling expression of genomic sequences which permit alternative splicing of E9 (NFR.CETP(+/-E9) transgene). With zinc induction, the mT.CETP(-E9) transgene gave rise to abundant E9-deleted CETP mRNA in liver and small intestine, but only relatively small amounts of E9-deleted protein were found in plasma. The E9-deleted form of CETP was inactive in lipid transfer and produced no changes in plasma lipoprotein profile. The NFR.CETP(+/-E9) transgene gave rise to full-length (FL) and E9-deleted forms of CETP mRNA in liver and spleen. In response to hypercholesterolemia induced by diet and breeding into an apoE gene knock-out background, the FL CETP mRNA was induced more than the E9-deleted mRNA, resulting in a 2-fold increase in ratio of FL/E9-deleted mRNA. The expression of CETP mRNA was found to be developmentally regulated. In NFR.CETP(+/-E9) transgenic mice CETP mRNA levels were markedly increased in the liver and small intestine in the perinatal period and decreased in adult mice, whereas CETP mRNA in the spleen was low in perinatal mice and increased in adults. The developmental increase in CETP mRNA in the liver and spleen was preceded by an increased ratio of FL/E9-deleted forms. Thus, the E9-deleted mRNA appears to be poorly translated and/or secreted, and the cognate protein is inactive in lipid transfer and lipoprotein metabolism. CETP gene expression was found to be highly regulated in a tissue-specific fashion during development. Increased CETP gene expression during development or in response to hypercholesterolemia is associated with preferential accumulation of the full-length CETP mRNA.
Highlights
The plasma cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl ester from high density lipoprotein to other lipoproteins
The mT.CETP(؊E9) transgene gave rise to abundant E9deleted CETP mRNA in liver and small intestine, but only relatively small amounts of E9-deleted protein were found in plasma
In NFR.CETP(؎E9) transgenic mice CETP mRNA levels were markedly increased in the liver and small intestine in the perinatal period and decreased in adult mice, whereas CETP mRNA in the spleen was low in perinatal mice and increased in adults
Summary
The plasma cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl ester from high density lipoprotein to other lipoproteins. The E9-deleted form of CETP was inactive in lipid transfer and produced no changes in plasma lipoprotein profile. Mice express very low levels of plasma cholesteryl ester transfer activity, and the introduction of a human CETP transgene results in decreased plasma HDL cholesterol levels, formation of smaller HDL species, and stimulation of cholesteryl ester formation in the plasma lipoproteins (Agellon et al, 1991). In response to a high cholesterol diet, CETP gene transcription is increased leading to increased mRNA levels in the liver and in peripheral tissues. In all human tissues expressing the CETP gene, two species of mRNA are detected: a full-length form, giving rise to active Mr 74,000 plasma CETP, and a shorter variant in which exon 9-derived sequences have been removed as a cassette (Inazu et al, 1992). In this study we have used transgenic mice to study the function and possible regulation of alternative splicing of the CETP gene
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