Genetic heterogeneity in the apolipoprotein C-III promoter and effects of insulin
In the present study, we have investigated the in vivo and in vitro role of two newly identified variants (G−944A and A−1180C) located in the upstream promoter region of the apolipoprotein C-III (apoC-III) gene. These variants were studied in 30 probands diagnosed with FCHL, their relatives, and spo...
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| Format: | Article |
| Language: | English |
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Elsevier
2001-09-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520302789 |
| _version_ | 1818669369880739840 |
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| author | Geesje M. Dallinga-Thie Martine Groenendijk Richard N.H.H.C. Blom Tjerk W.A. De Bruin Eric De Kant |
| author_facet | Geesje M. Dallinga-Thie Martine Groenendijk Richard N.H.H.C. Blom Tjerk W.A. De Bruin Eric De Kant |
| author_sort | Geesje M. Dallinga-Thie |
| collection | DOAJ |
| description | In the present study, we have investigated the in vivo and in vitro role of two newly identified variants (G−944A and A−1180C) located in the upstream promoter region of the apolipoprotein C-III (apoC-III) gene. These variants were studied in 30 probands diagnosed with FCHL, their relatives, and spouses. The allele frequencies of both variants were not different between the groups. No significant associations between plasma lipid traits and DNA variants were observed. We further analyzed the effect of the presence of these variants in the upstream enhancing region of the apoC-III gene, as five different in vivo occurring haplotypes, on the transcriptional activity of apoC-III in both HepG2 and Caco-2 cells. All five promoter constructs, including the wild type, showed similar enhancing activity of the apoC-III gene. The average transcription efficiency was enhanced 19-fold in HepG2 cells and 11-fold in Caco-2 cells. Previous studies have shown in vitro insulin-dependent down-regulation of the apoC-III gene transcription in HepG2 cells by DNA variation in an insulin response element (IRE) in the apoC-III promoter. We observed a 30% insulin-dependent down-regulation of apoC-III expression that was, however, independent of the presence of the two IRE variants. In contrast, in Caco-2 cells, a more variable insulin-dependent up-regulation was found that was also independent of the presence of the IRE variants. In conclusion, our data suggested that the apoC-III gene transcription in vitro is regulated by insulin but independent of the presence of the two IRE variants at −455 and −482. We were unable to detect associations between these apoC-III variants and plasma lipids and insulin in our FCHL population. This means that in vivo apoC-III transcription not only depends upon insulin but appears to be mediated by other mechanisms. —Dallinga-Thie, G. M., M. Groenendijk, R. N. H. H. C. Blom, T. W. A. De Bruin, and E. De Kant. Genetic heterogenicity in the apolipoprotein C-III promoter and effects of insulin. |
| first_indexed | 2024-12-17T06:51:08Z |
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| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T06:51:08Z |
| publishDate | 2001-09-01 |
| publisher | Elsevier |
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| series | Journal of Lipid Research |
| spelling | doaj.art-d9383185e5af4d88b73f3c09e31c7edb2022-12-21T21:59:35ZengElsevierJournal of Lipid Research0022-22752001-09-0142914501456Genetic heterogeneity in the apolipoprotein C-III promoter and effects of insulinGeesje M. Dallinga-Thie0Martine Groenendijk1Richard N.H.H.C. Blom2Tjerk W.A. De Bruin3Eric De Kant4Department of Internal Medicine, G02.228, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The NetherlandsDepartment of Internal Medicine, G02.228, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The NetherlandsDepartment of Internal Medicine, G02.228, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The NetherlandsTo whom correspondence should be addressed. e-mail:; Department of Internal Medicine, G02.228, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The NetherlandsDepartment of Internal Medicine, G02.228, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The NetherlandsIn the present study, we have investigated the in vivo and in vitro role of two newly identified variants (G−944A and A−1180C) located in the upstream promoter region of the apolipoprotein C-III (apoC-III) gene. These variants were studied in 30 probands diagnosed with FCHL, their relatives, and spouses. The allele frequencies of both variants were not different between the groups. No significant associations between plasma lipid traits and DNA variants were observed. We further analyzed the effect of the presence of these variants in the upstream enhancing region of the apoC-III gene, as five different in vivo occurring haplotypes, on the transcriptional activity of apoC-III in both HepG2 and Caco-2 cells. All five promoter constructs, including the wild type, showed similar enhancing activity of the apoC-III gene. The average transcription efficiency was enhanced 19-fold in HepG2 cells and 11-fold in Caco-2 cells. Previous studies have shown in vitro insulin-dependent down-regulation of the apoC-III gene transcription in HepG2 cells by DNA variation in an insulin response element (IRE) in the apoC-III promoter. We observed a 30% insulin-dependent down-regulation of apoC-III expression that was, however, independent of the presence of the two IRE variants. In contrast, in Caco-2 cells, a more variable insulin-dependent up-regulation was found that was also independent of the presence of the IRE variants. In conclusion, our data suggested that the apoC-III gene transcription in vitro is regulated by insulin but independent of the presence of the two IRE variants at −455 and −482. We were unable to detect associations between these apoC-III variants and plasma lipids and insulin in our FCHL population. This means that in vivo apoC-III transcription not only depends upon insulin but appears to be mediated by other mechanisms. —Dallinga-Thie, G. M., M. Groenendijk, R. N. H. H. C. Blom, T. W. A. De Bruin, and E. De Kant. Genetic heterogenicity in the apolipoprotein C-III promoter and effects of insulin.http://www.sciencedirect.com/science/article/pii/S0022227520302789gene regulationfamilial combined hyperlipidemiaHepG2Caco-2transcription |
| spellingShingle | Geesje M. Dallinga-Thie Martine Groenendijk Richard N.H.H.C. Blom Tjerk W.A. De Bruin Eric De Kant Genetic heterogeneity in the apolipoprotein C-III promoter and effects of insulin Journal of Lipid Research gene regulation familial combined hyperlipidemia HepG2 Caco-2 transcription |
| title | Genetic heterogeneity in the apolipoprotein C-III promoter and effects of insulin |
| title_full | Genetic heterogeneity in the apolipoprotein C-III promoter and effects of insulin |
| title_fullStr | Genetic heterogeneity in the apolipoprotein C-III promoter and effects of insulin |
| title_full_unstemmed | Genetic heterogeneity in the apolipoprotein C-III promoter and effects of insulin |
| title_short | Genetic heterogeneity in the apolipoprotein C-III promoter and effects of insulin |
| title_sort | genetic heterogeneity in the apolipoprotein c iii promoter and effects of insulin |
| topic | gene regulation familial combined hyperlipidemia HepG2 Caco-2 transcription |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520302789 |
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