Genetics
Both wild-type CETP and its poorly secreted splice variants trigger the same endoplasmic reticulum stress response (J Lipid Res 2008)
Original title: Expression of CETP and of splice variants induces the same level of ER stress despite secretion efficiency differences
Researchers characterised newly discovered alternatively spliced variants of cholesteryl ester transfer protein (CETP), which skip exon 9 and insert Alu-derived intronic exon sequences, alongside the previously known exon-9-skipping variant. None of the spliced variants were efficiently secreted, and co-expressing them inhibited secretion of wild-type CETP. Expression of the spliced variants induced genes linked to the endoplasmic reticulum (ER) stress response, including the neighbouring HERPUD1 gene. Unexpectedly, wild-type CETP, despite being secreted far more efficiently than the spliced variants, induced the same degree of ER stress response, while a control secreted protein did not. The findings show CETP expression itself induces ER stress, with its transfer activity and splicing pattern separately modulating that response.
Original abstract
The cholesteryl ester transfer protein (CETP) gene has been associated with a variety of phenotypes, including HDL-cholesterol levels and, more sporadically, with cardiovascular disease, obesity, and extreme longevity. Alterations of CETP activity levels can be caused by single-base polymorphisms as well as by alternative splicing. In addition to the previously characterized alternative splicing that skips exon 9, we found additional minor variants and characterized the activity of the resultant proteins. The novel variants skipped exon 9 sequences and inserted one of two in-frame exons from Alu-derived intronic sequences. None of the alternatively spliced variants are efficiently secreted, and coexpression of them inhibits wild-type CETP secretion. Expression of the alternative spliced variants causes an induction of genes linked to the endoplasmic reticulum (ER) stress response, including the neighboring HERPUD1 (homocysteine- and ER stress-inducible protein, ubiquitin-like domain-containing) gene. Unexpectedly, even though wild-type CETP is secreted much more efficiently than spliced variants, it induces the same degree of stress response as spliced variants, whereas a control secreted protein does not. CETP plays a complex role in modulating ER stress, with its expression inducing the response and its cholesteryl ester transfer activity and differential splicing modulating the response in other ways.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.