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ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors
Open accessAbstract
Hypertriglyceridemia is an independent risk factor for cardiovascular disease, and plasma triglycerides (TGs) correlate strongly with plasma apolipoprotein C-III (ApoC-III) levels. Antisense oligonucleotides (ASOs) for ApoC-III reduce plasma TGs in primates and mice, but the underlying mechanism of action remains controversial. We determined that a murine-specific ApoC-III-targeting ASO reduces fasting TG levels through a mechanism that is dependent on low-density lipoprotein receptors (LDLRs) and LDLR-related protein 1 (LRP1). ApoC-III ASO treatment lowered plasma TGs in mice lacking lipoprotein lipase (LPL), hepatic heparan sulfate proteoglycan (HSPG) receptors, LDLR, or LRP1 and in animals with combined deletion of the genes encoding HSPG receptors and LDLRs or LRP1. However, the ApoC-III ASO did not lower TG levels in mice lacking both LDLR and LRP1. LDLR and LRP1 were also required for ApoC-III ASO-induced reduction of plasma TGs in mice fed a high-fat diet, in postprandial clearance studies, and when ApoC-III-rich or ApoC-III-depleted lipoproteins were injected into mice. ASO reduction of ApoC-III had no effect on VLDL secretion, heparin-induced TG reduction, or uptake of lipids into heart and skeletal muscle. Our data indicate that ApoC-III inhibits turnover of TG-rich lipoproteins primarily through a hepatic clearance mechanism mediated by the LDLR/LRP1 axis.
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“In contrast, elevated levels of apolipoprotein C-III lead to chylomicronemia and severe hypertriglyceridemia by inhibiting LPL activity, 21 inhibiting hepatic uptake of triglyceride-rich lipoproteins, 22 and increasing hepatic secretion of triglyceride-rich lipoproteins. 21”
From Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome (2024) · cites this paper as [22]
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“Inhibition of Apo-CIII using anti-sense oligonucleotides reduced plasma triglycerides in a process dependent on LDLR and its related family member LRP-1101, and is a promising therapeutic for combined familial hyperlipidemias.”
From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [101]
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“In three patients with FCS, volanesorsen-reduced TG levels by up to 86%,72 through a mechanism independent of LPL activity.73”
From Clinical review on triglycerides (2020) · cites this paper as [73]
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“These data show that volanesorsenmediated lowering of apolipoprotein C-III effectively enhances clearance of triglyceride-rich lipoproteins in patients without LPL activity.27”
From Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome (2019) · cites this paper as [27]
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“the clearance of both TRLs and remnants, resulting in prolonged residence times of these particles in the circulation.(413,414) In fact, the defective catabolism of TRLs seems to be a more important contributor to the elevation of plasma TGs than the increased production rate leading to an excess of remnant particles.”
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“74,200,201 An ASO directed against apoCIII markedly reduced plasma TG levels in subjects lacking LpL activity, 188,189 thus providing indirect support for improved hepatic uptake at low plasma apoCIII levels.”
BackgroundVolanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome
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Metadata
- Authors
- Gordts, P. L. S. M., Nock, R., Son, N.-H., Ramms, B., Lew, I., Gonzales, J. C., Thacker, B. E., Basu, D., Lee, R. G., Mullick, A. E., Graham, M. J., Goldberg, I. J., Crooke, R. M., Witztum, J. L., & Esko, J. D.
- Affiliations
- University of California San Diego (US)
- NYU Langone Health (US)
- Bielefeld University (DE)
- Ionis Pharmaceuticals (United States) (US)
- Corresponding author
- Gordts, Philip L.S.M.
- Esko, Jeffrey D.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-07-11
- Volume
- 126
- Issue
- 8
- Pages
- 2855-2866
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC4966320
- OpenAlex
- W2471143596
- Cited by
- 274
- References
- 47
- Citations by year
- 2026: 32 · 2025: 20 · 2024: 24 · 2023: 19 · 2022: 27 · 2021: 35 · 2020: 35 · 2019: 30 · 2018: 21 · 2017: 22 · 2016: 8
- FWCI
- 22.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL045095, P01HL092969, P01HL107150, R37HL045095, P01HL088093)
- National Institute of General Medical Sciences (R01GM033063, R37GM033063)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein C-III, antisense oligonucleotides, triglyceride-rich lipoproteins, LDL receptor, hypertriglyceridemia, heparan sulfate proteoglycans, lipoprotein lipase, high-fat diet, cardiovascular risk
- MeSH terms
- Animals, Female, Genotype, Heparin, Ketones, Lipoproteins, Liver, Male, Mice, Inbred C57BL, Mice, Transgenic, Myocardium, Receptors, LDL, Risk Factors, Triglycerides, Hepatocytes, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Mice, Apolipoprotein C-III
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