Apolipoprotein C-III and the Metabolic Basis for Hypertriglyceridemia and the Dense Low-Density Lipoprotein Phenotype
Open accessAbstract
Background— Here, we aim to identify defects of apolipoprotein (apo) B lipoprotein metabolism that characterize hypertriglyceridemia, focusing on apoC-III and apoE. Methods and Results— We studied the transport of plasma apoB within 21 distinct subfractions as separated by anti–apoC-III and anti–apoE immunoaffinity chromatography and ultracentrifugation in 9 patients with moderate hypertriglyceridemia and 12 normotriglyceridemic control subjects. Hypertriglyceridemia was characterized by a 3-fold higher liver secretion of very low-density lipoprotein (VLDL) that had apoC-III but not apoE and a 50% lower secretion of VLDL with both apoC-III and apoE (both P <0.05). This shift in VLDL secretion pattern from apoE to apoC-III resulted in significantly reduced clearance of light VLDL (−39%; P <0.05), compatible with the antagonizing effects of apoC-III on apoE-induced clearance of triglyceride-rich lipoproteins. In addition, rate constants for clearance were reduced for apoE-containing triglyceride-rich lipoproteins in hypertriglyceridemia, associated with increased apoC-III contents of these particles. LDL distribution shifted from light and medium LDL to dense LDL in hypertriglyceridemia through a quartet of kinetic perturbations: increased flux from apoC-III–containing triglyceride-rich lipoproteins, a shift in liver LDL secretion pattern from light to dense LDL, an increased conversion rate from light and medium LDL to dense LDL, and retarded catabolism of dense LDL. Conclusions— These results support a central role for apoC-III in metabolic defects leading to hypertriglyceridemia. Triglyceride-rich lipoprotein metabolism shifts from an apoE-dominated system in normotriglyceridemic participants characterized by rapid clearance from circulation of VLDL to an apoC-III–dominated system in hypertriglyceridemic patients characterized by reduced clearance of triglyceride-rich lipoproteins and the formation of the dense LDL phenotype.
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Nearly all VLDL particles containing APOC-III undergo intravascular triglyceride lipolysis, generating LDL particles that also contain APOC-III.
“Studies have shown that nearly all VLDL particles containing APOC-III undergo intravascular triglyceride lipolysis, generating LDL particles that also contain APOC-III [25–27].”
From The Efficacy and Safety of Plozasiran on Lipid Profile in Dyslipidemic Disorders: A Systematic Review and Meta-Analysis (2026) · cites this paper as [25]
The Results (page not supplied) report that fewer than 7% of VLDL and IDL containing apoC-III but not apoE were removed before conversion to LDL, supporting near-complete conversion for that subgroup. The claim extends this to all apoC-III–containing VLDL, whereas the Discussion says apoE-containing triglyceride-rich particles mostly undergo direct removal. The Results also say that more than 80% of the resulting apoC-III–containing LDL was subsequently converted to LDL without apoC-III. (LLM, conf=0.88)
Experimental — accuracy not yet measuredApoCIII in VLDLs reduces clearance of VLDL particles by inhibiting the effect of apoE on receptor-mediated uptake.
“Apart from inhibiting LPL, apoCIII in VLDLs reduces clearance of VLDL particles by inhibiting the effect of apoE on receptor-mediated uptake [46].”
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References 28 · Cited by 223
- Authors
- Zheng, C., Khoo, C., Furtado, J., & Sacks, F. M.
- Affiliations
- Brigham and Women's Hospital (US)
- Venue
- Circulation
- Published
- 2010-04-20
- Volume
- 121
- Issue
- 15
- Pages
- 1722-1734
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC3153990
- OpenAlex
- W2165961239
- Cited by
- 223
- References
- 28
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 7 · 2023: 8 · 2022: 7 · 2021: 16 · 2020: 16 · 2019: 12 · 2018: 16 · 2017: 12 · 2016: 19 · 2015: 26 · 2014: 16 · 2013: 12 · 2012: 15
- FWCI
- 11.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (5r01hl034980-07)
- National Heart, Lung, and Blood Institute (R01HL56210, R01HL056210, R01HL-34980, R01HL070159)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK040561)
- National Center for Research Resources (RR02635, M01RR002635)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein C-III, apolipoprotein E, hypertriglyceridemia, very low density lipoprotein secretion, VLDL clearance, triglyceride-rich lipoproteins, lipoprotein metabolism, hepatic lipoprotein secretion, LDL catabolism
- MeSH terms
- Adult, Apolipoproteins B, Apolipoproteins E, Chromatography, Affinity, Dietary Carbohydrates, Dietary Fats, Female, Humans, Leucine, Lipoproteins, LDL, Liver, Male, Middle Aged, Phenotype, Phenylalanine, Triglycerides, Hypertriglyceridemia, Cholesterol, VLDL, Apolipoprotein C-III
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