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Exon-9-deleted CETP mRNA yields an inactive protein, while hypercholesterolemia and development favor full-length transcript accumulation (J Biol Chem 1996)
Original title: Alternative splicing of the human cholesteryl ester transfer protein gene in transgenic mice. Exon exclusion modulates gene expression in response to dietary or developmental change
The human CETP gene produces two mRNA forms, with or without exon 9 (E9)-derived sequences. Transgenic mice were engineered with a metallothionein promoter driving an E9-deleted CETP construct, and separately with natural flanking regions permitting alternative splicing of E9. The E9-deleted construct produced abundant E9-deleted CETP mRNA in liver and small intestine but only small amounts of protein in plasma, and this protein form was inactive in lipid transfer with no effect on the lipoprotein profile. In mice permitting alternative splicing, diet- and apoE-knockout-induced hypercholesterolemia induced full-length (FL) CETP mRNA more than the E9-deleted form, producing a 2-fold increase in the FL/E9-deleted mRNA ratio. CETP mRNA expression was also developmentally regulated in a tissue-specific fashion, and increased CETP expression during development or hypercholesterolemia favored accumulation of the active, full-length transcript.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.