Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia.
Open accessAbstract
Overexpression of plasma apolipoprotein CIII (apo CIII) causes hypertriglyceridemia in transgenic mice. A genetically variant form of the human apo CIII promoter, containing five single base pair changes, has been shown to be associated with severe hypertriglyceridemia in a patient population. In animals and in cultured cells the apo CIII gene is transcriptionally downregulated by insulin. In this study we demonstrate that, unlike the wild-type promoter, the variant promoter was defective in its response to insulin treatment, remaining constitutively active at all concentrations of insulin. The loss of insulin regulation was mapped to polymorphic sites at -482 and -455, which fall within a previously identified insulin response element. Loss of insulin regulation could result in overexpression of the apo CIII gene and contribute to the development of hypertriglyceridemia. The variant apo CIII promoter is common in the human population and may represent a major contributing factor to the development of hypertriglyceridemia.
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The associations of the variant alleles with higher apolipoprotein C3 expression are independent and not additive.
“Because these associations are independent and not additive, we divided the study participants into two genetically defined groups for the purposes of analysis: those who were homozygous for the low-expression (wild-type) allele at both SNPs and those who were carriers of one or more high-expression (variant) alleles at either SNP.”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [12]
The variant alleles at rs2854116 (T-455C) and rs2854117 (C-482T) are each associated with higher apolipoprotein C3 expression in vitro than the respective wild-type alleles.
“The variant alleles at rs2854116 (T-455C) and at rs2854117 (C-482T) are each associated with higher apolipoprotein C3 expression in vitro than are the respective wild-type alleles.12”
From Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease (2010) · cites this paper as [12]
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References 26 · Cited by 278
- Authors
- Li, W. W., Dammerman, M. M., Smith, J. D., Metzger, S., Breslow, J. L., & Leff, T.
- Affiliations
- Pfizer (United States) (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1995-12-01
- Volume
- 96
- Issue
- 6
- Pages
- 2601-2605
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC185964
- OpenAlex
- W2127958304
- Cited by
- 278
- References
- 26
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 6 · 2022: 8 · 2021: 5 · 2020: 8 · 2019: 3 · 2018: 3 · 2017: 4 · 2016: 9 · 2015: 7 · 2014: 5 · 2013: 11 · 2012: 8
- FWCI
- 7.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (5r01hl045394-04, 5r01hl033714-17)
- National Heart, Lung, and Blood Institute (HL 33714, R01HL032435, HL 45394, HL32435)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein C-III, promoter polymorphism, hypertriglyceridemia, insulin regulation, insulin response element, transcriptional regulation, genetic variation, plasma triglycerides, transgenic mice
- MeSH terms
- Alleles, Animals, Apolipoproteins C, Base Sequence, Cell Nucleus, Gene Expression Regulation, Humans, Hyperlipoproteinemia Type IV, Insulin, Liver, Luciferases, Mice, Transgenic, Molecular Sequence Data, Promoter Regions, Genetic, Transcription, Genetic, Transfection, Genetic Variation, Restriction Mapping, Chloramphenicol O-Acetyltransferase, Genomic Library, Gene Expression, Mice, Apolipoprotein C-III
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