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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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Self-citationPlozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia
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InfluentialThe Roles of ApoC-III on the Metabolism of Triglyceride-Rich Lipoproteins in Humans
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“The ability of apoCIII inhibition to reduced plasma TG levels dramatically in patients with no LpL suggested that hepatic uptake must have increased in association with reduced circulating apoCIII concentrations (10, 43).”
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“First, ASO-mediated apoC-III reduction does not improve hepatic TRL clearance in ApoeNdst1Alb-Cre mice, while it does improve TRL clearance in Ndst1Alb-Cre mice (5).”
InfluentialSelf-citationRole of apolipoprotein C-III overproduction in diabetic dyslipidaemia
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“Additionally, the low LDL cholesterol levels observed in families with FHBL2 [24] could be partially explained from the decreased synthesis and secretion of VLDL from the liver since, following lipolysis by LPL, VLDL and its metabolic intermediate, IDL, have two possible fates: clearance by the liver or further metabo…”
BackgroundInfluentialmicroRNA-483 ameliorates hypercholesterolemia by inhibiting PCSK9 production
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“Lipoprotein profiles were determined as described (35).”
Self-citationNew Trends in Dyslipidemia Treatment
Jang, A. Y., Lim, S., Jo, S.-H., Han, S. H., & Koh, K. K. (2020) · Circulation Journal · doi:10.1253/circj.cj-20-1037 · Cited by 62
Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL
Larsson, M., Allan, C. M., Jung, R. S., Heizer, P. J., Beigneux, A. P., Young, S. G., & Fong, L. G. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m078220 · Cited by 57
CD47 peptide-cloaked lipid nanoparticles promote cell-specific mRNA delivery
Papp, T. E., Zeng, J., Shahnawaz, H., Akyianu, A., Breda, L., Yadegari, A., Steward, J., Shi, R., Li, Q., Mui, B. L., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.03.018 · Cited by 59
The heparan sulfate proteoglycan grip on hyperlipidemia and atherosclerosis
Gordts, P. L. S. M., & Esko, J. D. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.05.010 · Cited by 53
“Recently, it has become apparent that ApoCIII inhibits clearance of TRL remnants via LDLR and LRP1 and not by inhibiting LPL [84, 95, 96].”
BackgroundInfluentialSelf-citationApoCIII: A multifaceted protein in cardiometabolic disease
D’Erasmo, L., Costanzo, A. D., Gallo, A., Bruckert, É., & Arca, M. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154395 · Cited by 52
Basu, D., & Bornfeldt, K. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00504 · Cited by 51
“In order to tackle the issue of whether TRLs or RLPs are causatively involved in exacerbating atherosclerosis, animal models have been used to investigate potential atherogenic effects of TRLs and RLPs and to provide mechanistic insight through an approach that has sometimes been termed “reverse translation,” “human-f…”
BackgroundInfluentialSelf-citationPrice, N. L., Zhang, X., Fernández-Tussy, P., Singh, A. K., Burnap, S. A., Rotllan, N., Goedeke, L., Sun, J., Canfrán-Duque, A., Aryal, B., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2006478118 · Cited by 50
“Fat tolerance test was performed as previously described (32).”
MethodChait, A. (2022) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2022.02.010 · Cited by 50
Prohaska, T. A., Alexander, V. J., Karwatowska‐Prokopczuk, E., Tami, J. A., Xia, S., Witztum, J. L., & Tsimikas, S. (2023) · Journal of clinical lipidology · doi:10.1016/j.jacl.2023.04.007 · Cited by 48
Self-citationAu, D. T., Strickland, D. K., & Muratoglu, S. C. (2017) · Journal of Diabetes Research · doi:10.1155/2017/8356537 · Cited by 50
“Their studies revealed that like adipocytes, insulin stimulated LRP1 translocation to the cell surface in human hepatic HuH7 tumor cells, a rat hepatoma cell line (FAO cells), as well as primary hepatocytes isolated from wild-type (WT) and low-density lipoprotein receptor knockout (LDLR−/−) mice.”
BackgroundInfluentialNew insights into ANGPLT3 in controlling lipoprotein metabolism and risk of cardiovascular diseases
Su, X., & Peng, D. (2018) · Lipids in Health and Disease · doi:10.1186/s12944-018-0659-y · Cited by 45
“Wang Y, Gusarova V, Banfi S, Gromada J, Cohen JC, Hobbs HH. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion.”
InfluentialGengatharan, J. M., Handzlik, M. K., Chih, Z. Y., Ruchhoeft, M. L., Secrest, P., Ashley, E. L., Green, C. R., Wallace, M., Gordts, P. L. S. M., & Metallo, C. M. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.10.016 · Cited by 48
Self-citationApolipoprotein C3: form begets function
Bornfeldt, K. (2023) · Journal of Lipid Research · doi:10.1016/j.jlr.2023.100475 · Cited by 53
“This conclusion is backed up by a mouse study, in which APOC3 silencing lowered both TRL triglyceride and cholesterol in LPL-deficient mice (44).”
BackgroundLi, P., Huang, J., Xiao, N., Cai, X., Yang, Y., Deng, J., Zhang, L., & Du, B. (2020) · Food & Function · doi:10.1039/d0fo01178a · Cited by 49
Astrocytic lipid metabolism determines susceptibility to diet-induced obesity
Varela, L., Kim, J. G., Fernández‐Tussy, P., Aryal, B. K., Liu, Z. W., Fernandez-Hernando, C. F., & Horváth, T. L. (2021) · Science Advances · doi:10.1126/sciadv.abj2814 · Cited by 44
“Aliquots (100 ml) of the supenatant were used for the lipase activity assay with 100 ml of 10% intralipid/[3H]-triolein emulsion for 1 hour at 25°C.The activities were normalized for starting tissue weights ( 32 , 36 , 48 ).”
MethodLipid Metabolism and Emerging Targets for Lipid-Lowering Therapy
Gaudet, D., Drouin‐Chartier, J., & Couture, P. (2017) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2016.12.019 · Cited by 43
The Regulation of Triacylglycerol Metabolism and Lipoprotein Lipase Activity
Wen, Y., Chen, Y., & Konrad, R. J. (2022) · Advanced Biology · doi:10.1002/adbi.202200093 · Cited by 43
Role of LpL (Lipoprotein Lipase) in Macrophage Polarization In Vitro and In Vivo
Chang, H. R., Josefs, T., Scerbo, D. A., Gumaste, N., Hu, Y., Huggins, L.-A., Barrett, T. J., Chiang, S. S., Grossman, J., Bagdasarov, S., et al. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.119.312389 · Cited by 42
Self-citationAl-Mrabeh, A. H. (2021) · Biomedicines · doi:10.3390/biomedicines9020226 · Cited by 43
Olkkonen, V. M., Sinisalo, J. P., & Jauhiainen, M. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.03.019 · Cited by 41
Marsche, G., Heine, G. H., Stadler, J. T., & Holzer, M. (2020) · Biomolecules · doi:10.3390/biom10091348 · Cited by 41
“in plasma associated with apoB-containing lipoproteins and HDL, and reduces the turnover of triglyceride-rich lipoproteins mainly by inhibiting a hepatic clearance mechanism mediated by the LDL-receptor/LDL-receptor-related protein 1 axis [66].”
BackgroundThe role of lysosomal membrane proteins in glucose and lipid metabolism
Gu, J., Geng, M., Qi, M., Wang, L., Zhang, Y., & Gao, J. (2021) · The FASEB Journal · doi:10.1096/fj.202002602r · Cited by 40
Quartet of APOCs and the Different Roles They Play in Diabetes
Hsu, C.-C., Kanter, J. E., Kothari, V. M., & Bornfeldt, K. (2023) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.122.318290 · Cited by 41
Apolipoprotein CIII Deficiency Protects Against Atherosclerosis in Knockout Rabbits
Yan, H., Niimi, M., Matsuhisa, F., Zhou, H., Kitajima, S., Chen, Y., Wang, C., Yang, X., Yao, J. Q., Yang, D., et al. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.314368 · Cited by 39
Targeting apoC-III and ANGPTL3 in the treatment of hypertriglyceridemia
Nurmohamed, N. S., Dallinga‐Thie, G. M., & Stroes, E. S. G. (2020) · Expert Review of Cardiovascular Therapy · doi:10.1080/14779072.2020.1768848 · Cited by 42
Heidari, A. (2020) · Advanced Science Engineering and Medicine · doi:10.1166/asem.2020.2635 · Cited by 36
Advances in Dyslipidaemia Treatments: Focusing on ApoC3 and ANGPTL3 Inhibitors
Tomlinson, B., Wu, Q., Zhong, Y.-M., & Li, Y. (2024) · Journal of Lipid and Atherosclerosis · doi:10.12997/jla.2024.13.1.2 · Cited by 39
Chan, D. C., Watts, G. F., Somaratne, R. M., Wasserman, S. M., Scott, R. C., & Barrett, P. H. R. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.310882 · Cited by 39
“ApoC-III is involved in chylomicron metabolism through the inhibition of LPL activity and chylomicron remnant uptake by hepatic lipoprotein receptors.(5,6) In vitro studies have also demonstrated that expression of apoC-III increases apoB-48 secretion.”
BackgroundApolipoprotein C-III and cardiovascular diseases: when genetics meet molecular pathologies
Dib, I., Khalil, A., Chouaib, R., El-Makhour, Y., & Noureddine, H. (2021) · Molecular Biology Reports · doi:10.1007/s11033-020-06071-5 · Cited by 37
Kegulian, N. C., Ramms, B., Horton, S. B., Trenchevska, O., Nedelkov, D., Graham, M. J., Lee, R. G., Esko, J. D., Yassine, H. N., & Gordts, P. L. S. M. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.119.312723 · Cited by 36
Self-citationReimund, M., Kovrov, O., Olivecrona, G., & Lookene, A. (2017) · Journal of Lipid Research · doi:10.1194/jlr.d071787 · Cited by 32
Pathways and Molecular Mechanisms Governing LDL Receptor Regulation
Schmidt, H. M., Jarrett, K. E., de Aguiar Vallim, T. Q., & Tarling, E. J. (2025) · Circulation Research · doi:10.1161/circresaha.124.323578 · Cited by 33
“…is an independent risk factor for CVD. Inhibition of Apo CIII using antisense oligonucleotides reduced plasma triglycerides in a process dependent on LDLR and its related family member LRP-1 (LDLR-related protein 1) 101 and is a promising therapeutic for combined familial hyperlipidemias.”
Yingchun, H., Ma, Y., Wen, J., He, X., & Xiaohong, Z. (2018) · Lipids in Health and Disease · doi:10.1186/s12944-018-0867-5 · Cited by 35
Hegele, R. A. (2016) · Journal of Lipid Research · doi:10.1194/jlr.c070946 · Cited by 31
“This now appears to be inhibition by apoC-III of receptor-mediated hepatic clearance of TG-rich lipoproteins (41).”
BackgroundCao, Y., Zhang, H., Jin, J., Liu, H., Zhang, Y., Xu, R., Gao, Y., Guo, Y., Zhu, C., Hua, Q., et al. (2020) · Journal of Lipid Research · doi:10.1194/jlr.ra120000746 · Cited by 31
Guanidinylated Apolipoprotein C3 (ApoC3) Associates with Kidney and Vascular Injury
Schunk, S. J., Hermann, J., Sarakpi, T., Triem, S., Lellig, M., Hahm, E., Zewinger, S., Schmit, D., Becker, E., Möllmann, J., et al. (2021) · Journal of the American Society of Nephrology · doi:10.1681/asn.2021040503 · Cited by 31
“ApoC3 plays an important role in the metabolism of triglyceride-rich lipoproteins mainly by inhibiting lipoprotein lipase and hepatic lipase leading to hypertriglyceridemia.(16) Carriers of null mutations in APOC3 are characterized by lower levels of triglycerides, higher HDL-C, and lower LDLC.”
BackgroundMüller‐Wieland, D., Leiter, L. A., Cariou, B., Letierce, A., Colhoun, H. M., Prato, S. D., Henry, R. R., Tinahones, F. J., Aurand, L. A., Maroni, J. M., et al. (2017) · Cardiovascular Diabetology · doi:10.1186/s12933-017-0552-4 · Cited by 30
“LDLR and LDLR–related protein 1) [41]; whether alirocumab and PCSK9 inhibitors impact this mechanism may be an area of future research.”
BackgroundmTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia
Paolella, L. M., Mukherjee, S., Tran, C. M., Bellaver, B., Hugo, M., Luongo, T. S., Shewale, S. V., Lu, W., Chellappa, K., & Baur, J. A. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.12.003 · Cited by 33
“It has long been demonstrated that NEFA can suppress LPL through multiple mechanisms, including product inhibition, displacement of the active enzyme from the endothelium, and preventing its interaction with activating factors such as ApoC-II [37,38,47,48].”
BackgroundPostprandial dysmetabolism: Too early or too late?
Pappas, C., Kandaraki, E., Tsirona, S., Kountouras, D., Kassi, G., & Diamanti‐Kandarakis, E. (2016) · HORMONES · doi:10.14310/horm.2002.1697 · Cited by 30
Li, D., Rodia, C. N., Johnson, Z. K., Bae, M., Muter, A., Heussinger, A. E., Tambini, N. S., Longo, A. M., Dong, H., Lee, J., et al. (2019) · Journal of Lipid Research · doi:10.1194/jlr.m092460 · Cited by 29
“apoC-III regulates enterocyte basolateral lipid uptake 1511 of remnant clearance by LDLr in the liver (13).”
BackgroundLightbourne, M., Startzell, M. S., Bruce, K. D., Brite, B., Muniyappa, R., Skarulis, M. C., Shamburek, R. D., Gharib, A. M., Ouwerkerk, R., Walter, M. F., et al. (2022) · Journal of clinical lipidology · doi:10.1016/j.jacl.2022.06.011 · Cited by 27
Spagnuolo, C. M., & Hegele, R. A. (2023) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2023.2206015 · Cited by 27
“For instance, apo C-III was shown to interfere with the catabolism of TG-rich lipoproteins by impeding an LDL-receptor dependent pathway [29].”
BackgroundNew approaches to triglyceride reduction: is there any hope left?
Filtz, A., Parihar, S., Greenberg, G. S., Park, C. M., Scotti, A., Lorenzatti, D., Badimon, J. J., Soffer, D. E., Toth, P. P., Lavie, C. J., et al. (2024) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2024.100648 · Cited by 26
“ApoC3 also inhibits the uptake of TRL via LDL receptor and LDL receptor-related protein-1 [100].”
Background
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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