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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Elevated levels of apolipoprotein C-III lead to chylomicronemia and severe hypertriglyceridemia by inhibiting LPL activity, inhibiting hepatic uptake of triglyceride-rich lipoproteins, and increasing hepatic secretion of triglyceride-rich lipoproteins.
“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]
In three patients with FCS, volanesorsen reduced TG levels by up to 86% through a mechanism independent of LPL activity.
“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]
The trial data indicate that volanesorsen-mediated apolipoprotein C-III reduction enhances clearance of triglyceride-rich lipoproteins in patients lacking LPL activity.
“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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BackgroundAddressing dyslipidemic risk beyond LDL-cholesterol
Tall, A. R., Thomas, D. G., Gonzalez-Cabodevilla, A. G., & Goldberg, I. J. (2022) · Journal of Clinical Investigation · doi:10.1172/jci148559 · Cited by 150 · see citing works
“Duewell P, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.”
BackgroundSelf-citationAbsence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis
Aryal, B. K., Singh, A. K., Zhang, X., Varela, L., Rotllán, N., Goedeke, L., Chaube, B., Camporez, J. P., Vatner, D. F., Horváth, T. L., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.97918 · Cited by 131 · see citing works
“PHP and tissue LPL activity was assayed as previously described (54).”
Chait, A., & Eckel, R. H. (2019) · Annals of Internal Medicine · doi:10.7326/m19-0203 · Cited by 128 · see citing works
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz455 · Cited by 8,961 · see citing works
Endothelial Cell Receptors in Tissue Lipid Uptake and Metabolism
Abumrad, N. A., Cabodevilla, A. G., Samovski, D., Pietka, T., Basu, D., & Goldberg, I. J. (2021) · Circulation Research · doi:10.1161/circresaha.120.318003 · Cited by 125 · see citing works
Self-citationZhao, Y., Zhuang, Z., Li, Y., Xiao, W., Song, Z., Huang, N., Wang, W., Dong, X., Jia, J., Clarke, R., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-46686-x · Cited by 117 · see citing works
“This needs to be mentioned in the Discussion section.”
Singh, A. K., Aryal, B. K., Chaube, B., Rotllán, N., Varela, L., Horváth, T. L., Suárez, Y., & Fernandez-Hernando, C. F. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2018.03.011 · Cited by 115 · see citing works
“(ETH Zurich) to yield offspring inheriting both the targeted allele and the UCP1-ER-Cre transgene (Angptl4loxP/loxPUCP1CRE/ERT2) generation of UCP1-ERCre mice is described in previous publication [28].”
BackgroundMethodInfluentialTargeting white, brown and perivascular adipose tissue in atherosclerosis development
van Dam, A. D., Boon, M. R., Berbée, J. F. P., Rensen, P. C. N., & van Harmelen, V. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.03.051 · Cited by 114 · see citing works
“In addition to inhibition of the clearance of these lipoproteins from plasma (Berbée et al., 2005; Gordts et al., 2016), they have pro-inflammatory properties.”
BackgroundKhetarpal, S. A., Zeng, X., Millar, J. S., Vitali, C., Somasundara, A. V. H., Zanoni, P., Landro, J. A., Barucci, N., Zavadoski, W. J., Sun, Z., et al. (2017) · Nature Medicine · doi:10.1038/nm.4390 · Cited by 109 · see citing works
Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes
Kanter, J. E., Shao, B., Kramer, F., Barnhart, S., Shimizu‐Albergine, M., Vaisar, T., Graham, M. J., Crooke, R. M., Manuel, C. R., Haeusler, R. A., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci127308 · Cited by 105 · see citing works
“, prior to experiencing a CAD event and priis that insulin reduces plasma APOC3 levels by increasing hepatic uptake of remnant lipoproteins through translocation of LDLRrelated protein 1 (50), a protein involved in APOC3 clearance (23).”
BackgroundMethodSelf-citationEmerging Evidence that ApoC-III Inhibitors Provide Novel Options to Reduce the Residual CVD
Taskinen, M., Packard, C. J., & Borén, J. (2019) · Current Atherosclerosis Reports · doi:10.1007/s11883-019-0791-9 · Cited by 104 · see citing works
Apolipoprotein C-III in triglyceride-rich lipoprotein metabolism
Ramms, B., & Gordts, P. L. S. M. (2018) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000502 · Cited by 103 · see citing works
Self-citationHe, P., Jiang, T., Ouyang, X.-P., Liang, Y., Zou, J.-Q., Wang, Y., Shen, Q., Liao, L., & Zheng, X. (2018) · Clinica Chimica Acta · doi:10.1016/j.cca.2018.02.006 · Cited by 100 · see citing works
Effects of <i>APOC3</i> Heterozygous Deficiency on Plasma Lipid and Lipoprotein Metabolism
Reyes-Soffer, G., Sztalryd, C., Horenstein, R. B., Holleran, S., Matveyenko, A., Thomas, T., Nandakumar, R., Ngai, C., Karmally, W., Ginsberg, H. N., et al. (2019) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.118.311476 · Cited by 97 · see citing works
“Our results also contrast with recent studies of the effects of apo CIII antisense in mice with targeted deletion of LpL, LDL receptors, the LDL receptor-related protein-1, and heparin sulfate proteoglycan receptors.(41) Their results led the authors to conclude that apo CIII inhibited hepatic uptake of remnant lipopr…”
ResultThermostable ionizable lipid-like nanoparticle (iLAND) for RNAi treatment of hyperlipidemia
Hu, B., Li, B., Li, K., Liu, Y., Li, C., Zheng, L., Zhang, M., Yang, T., Guo, S., Dong, X., et al. (2022) · Science Advances · doi:10.1126/sciadv.abm1418 · Cited by 95 · see citing works
“However, patients with significantly reduced LDL-C still had residual cardio-vascular risk that gradually increased with each additional feature of the metabolic syndrome ( 13 ).”
Kinetics of plasma triglycerides in abdominal obesity
Björnson, E., Adiels, M., Taskinen, M., & Borén, J. (2016) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000375 · Cited by 94 · see citing works
Beyond Lipoprotein(a) plasma measurements: Lipoprotein(a) and inflammation
Reyes‐Soffer, G., & Westerterp, M. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105689 · Cited by 92 · see citing works
Sinha, S. K., Miikeda, A., Fouladian, Z., Mehrabian, M., Edillor, C. R., Shih, D. M., Zhou, Z., Paul, M. K., Charugundla, S., Davis, R. C., et al. (2020) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.120.315255 · Cited by 82 · see citing works
Ginsberg, H. N., & Goldberg, I. J. (2022) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.122.317966 · Cited by 83 · see citing works
Self-citationAlvi, S. S., Ansari, I. A., Ahmad, M. K., Iqbal, J., & Khan, M. S. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.11.116 · Cited by 78 · see citing works
APOC-III: a Gatekeeper in Controlling Triglyceride Metabolism
Giammanco, A., Spina, R., Cefalu, A. B., & Averna, M. R. (2023) · Current Atherosclerosis Reports · doi:10.1007/s11883-023-01080-8 · Cited by 83 · see citing works
Triglyceride and Triglyceride-Rich Lipoproteins in Atherosclerosis
Zhang, B., Yin, F., Qiao, Y.-N., & Guo, S. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.909151 · Cited by 79 · see citing works
Oral, E. A., Garg, A., Tami, J. A., Huang, E. A., O'Dea, L. S. L., Schmidt, H., Tiulpakov, A. N., Mertens, A. C., Alexander, V. J., Watts, L. M., et al. (2022) · Journal of clinical lipidology · doi:10.1016/j.jacl.2022.08.008 · Cited by 75 · see citing works
Self-citationApolipoprotein C-III Levels and Incident Coronary Artery Disease Risk
van Capelleveen, J. C., Moens, S. J. B., Yang, X., Kastelein, J. J. P., Wareham, N. J., Zwinderman, A. H., Stroes, E. S. G., Witztum, J. L., Hovingh, G. K., Khaw, K., et al. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.309007 · Cited by 71 · see citing works
Self-citationModification of lipoprotein metabolism and function driving atherogenesis in diabetes
Luciani, L., Pedrelli, M., & Parini, P. (2024) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.117545 · Cited by 72 · see citing works
Wolska, A. T., Lo, L., Sviridov, D. O., Pourmousa, M., Pryor, M., Ghosh, S. S., Kakkar, R. K., Davidson, M., Wilson, S. R., Pastor, R. W., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aaw7905 · Cited by 69 · see citing works
Self-citationHypertriglyceridemia—causes, significance, and approaches to therapy
Santos-Baez, L. S., & Ginsberg, H. N. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00616 · Cited by 66 · see citing works
“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).”
BackgroundInfluentialExploring apolipoprotein C-III: pathophysiological and pharmacological relevance
Packard, C. J., Pirillo, A., Tsimikas, S., Ference, B. A., & Catapano, A. L. (2023) · Cardiovascular Research · doi:10.1093/cvr/cvad177 · Cited by 65 · see citing works
ANGPTL3 and Apolipoprotein C-III as Novel Lipid-Lowering Targets
Akoumianakis, I., Zvintzou, E., Kypreos, K. E., & Filippatos, T. D. (2021) · Current Atherosclerosis Reports · doi:10.1007/s11883-021-00914-7 · Cited by 62 · see citing works
RNA-targeted therapeutics for lipid disorders
Tsimikas, S. (2018) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000549 · Cited by 61 · see citing works
ApoC-III ASO promotes tissue LPL activity in the absence of apoE-mediated TRL clearance
Ramms, B., Patel, S., Nora, C., Pessentheiner, A. R., Chang, M. W., Green, C. R., Golden, G. J., Secrest, P., Krauss, R. M., Metallo, C. M., et al. (2019) · Journal of Lipid Research · doi:10.1194/jlr.m093740 · Cited by 59 · see citing works
“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
Adiels, M., Taskinen, M., Björnson, E., Andersson, L., Matikainen, N., Söderlund, S., Kahri, J., Hakkarainen, A., Lundbom, N., Sihlbom, C., et al. (2019) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.13744 · Cited by 55 · see citing works
Effects of Angiopoietin-Like 3 on Triglyceride Regulation, Glucose Homeostasis, and Diabetes
Christopoulou, E. C., Elisaf, M., & Filippatos, T. D. (2019) · Disease Markers · doi:10.1155/2019/6578327 · Cited by 56 · see citing works
“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
Dong, J., He, M., Li, J., Pessentheiner, A. R., Wang, C., Zhang, J., Sun, Y., Wang, W.-T., Zhang, Y., Liu, J., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.143812 · Cited by 54 · see citing works
“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 56 · see citing works
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 54 · see citing works
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 52 · see citing works
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 51 · see citing works
“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 · see citing works
Basu, D., & Bornfeldt, K. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00504 · Cited by 51 · see citing works
“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 · see citing works
“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 · see citing works
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 · see citing works
Self-citationAu, D. T., Strickland, D. K., & Muratoglu, S. C. (2017) · Journal of Diabetes Research · doi:10.1155/2017/8356537 · Cited by 47 · see citing works
“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 · see citing works
“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 46 · see citing works
Self-citationApolipoprotein C3: form begets function
Bornfeldt, K. (2023) · Journal of Lipid Research · doi:10.1016/j.jlr.2023.100475 · Cited by 47 · see citing works
“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 47 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
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 41 · see citing works
Self-citationAl-Mrabeh, A. H. (2021) · Biomedicines · doi:10.3390/biomedicines9020226 · Cited by 42 · see citing works
Olkkonen, V. M., Sinisalo, J. P., & Jauhiainen, M. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.03.019 · Cited by 41 · see citing works
Marsche, G., Heine, G. H., Stadler, J. T., & Holzer, M. (2020) · Biomolecules · doi:10.3390/biom10091348 · Cited by 40 · see citing works
“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 · see citing works
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 37 · see citing works
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 · see citing works
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 39 · see citing works
Heidari, A. (2020) · Advanced Science Engineering and Medicine · doi:10.1166/asem.2020.2635 · Cited by 36 · see citing works
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 38 · see citing works
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 36 · see citing works
“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 36 · see citing works
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 34 · see citing works
Self-citationReimund, M., Kovrov, O., Olivecrona, G., & Lõokene, A. (2016) · Journal of Lipid Research · doi:10.1194/jlr.d071787 · Cited by 33 · see citing works
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 32 · see citing works
Hegele, R. A. (2016) · Journal of Lipid Research · doi:10.1194/jlr.c070946 · Cited by 31 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
“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 30 · see citing works
“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].”
BackgroundPathways and Molecular Mechanisms Governing LDL Receptor Regulation
Schmidt, H. M., Jarrett, K. E., Vallim, T. Q. D. A., & Tarling, E. J. (2025) · Circulation Research · doi:10.1161/circresaha.124.323578 · Cited by 29 · see citing works
“…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.”
Postprandial 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 29 · see citing works
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 · see citing works
“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 · see citing works
Spagnuolo, C. M., & Hegele, R. A. (2023) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2023.2206015 · Cited by 27 · see citing works
“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 · see citing works
“ApoC3 also inhibits the uptake of TRL via LDL receptor and LDL receptor-related protein-1 [100].”
Background
- 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 › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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