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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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Citations
Cites
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Self-citationInhibition of lipoprotein lipase by an apoprotein of human very low density lipoprotein
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Tirronen, A., Vuorio, T., Kettunen, S., Hokkanen, K., Ramms, B., Niskanen, H., Laakso, H., Kaikkonen, M. U., Jauhiainen, M., Gordts, P. L. S. M., et al. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.311549 · Cited by 26
Self-citationγ-secretase inhibition lowers plasma triglyceride-rich lipoproteins by stabilizing the LDL receptor
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“pathways, as demonstrated in animal models, including via a hepatic mechanism involving LDL receptor related protein 1 [58].”
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“The first is a positively charged region that spans amino acids 186 – 227 and functions as a receptor-binding domain that facilitates interactions with LDL or heparin.”
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“In addition to plasma nonesterified FA, triglyceriderich lipoprotein (TRL)-remnants, products of lipolysis of nascent VLDL and chylomicrons, can enter the liver via several pathways [29], contributing a modest amount of FA after lysosomal degradation of”
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“Increased levels of APOC3 in TRLs are known to inhibit LPL’s ability to hydrolyze TGs in these particles, slowing their conversion to remnants and subsequent hepatic clearance (14) and also to prevent TRL clearance through LDL family receptors (28).”
BackgroundInfluentialSelf-citationNew Therapeutic Approaches to the Treatment of Dyslipidemia 1: ApoC-III and ANGPTL3
Kim, J. Y., & Kim, N. H. (2023) · Journal of Lipid and Atherosclerosis · doi:10.12997/jla.2023.12.1.23 · Cited by 23
Lipolytic enzymes and free fatty acids at the endothelial interface
Goldberg, I. J., Cabodevilla, A. G., Samovski, D., Cifarelli, V., Basu, D., & Abumrad, N. A. (2021) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2021.05.018 · Cited by 25
Self-citationThe Remnant Lipoprotein Hypothesis of Diabetes-Associated Cardiovascular Disease
Bornfeldt, K. (2022) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.122.317163 · Cited by 22
Ramms, B., Patel, S., Sun, X., Pessentheiner, A. R., Ducasa, G. M., Mullick, A. E., Lee, R. G., Crooke, R. M., Tsimikas, S., Witztum, J. L., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.158414 · Cited by 22
“Second, in Ldlr–/– Ndst1fl/fl Alb-Cre+ mice, apoC-III inhibition lowered triglycerides by reducing TRL lipoprotein particle numbers, improving hepatic TRL clearance via LRP1 (Figure 1B) (11).”
BackgroundMethodInfluentialSelf-citationRemnant lipoprotein particles and cardiovascular disease risk
Krauss, R. M., & King, S. M. (2022) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2022.101682 · Cited by 27
Updates in Small Interfering RNA for the Treatment of Dyslipidemias
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“…lipoprotein lipase activity; it inhibits the removal of TG-rich particles from the bloodstream; it promotes hepatic VLDL secretion into the blood; it inhibits the turnover of TRL primarily through a hepatic clearance mechanism mediated by the LDL receptor/ LDL receptor–related protein 1 axis [84].”
BackgroundMetabolism of Triglyceride-Rich Lipoproteins
Borén, J., & Taskinen, M. (2021) · Handbook of experimental pharmacology · doi:10.1007/164_2021_520 · Cited by 22
“ApoC-III is displacing apo-CII, an activator of LPL, from lipoprotein surfaces and thus impairing the actual lipolytic process (Sacks 2015; Gordts et al. 2016; Larsson et al. 2013).”
BackgroundSorokin, A. V., Patel, N. H., Abdelrahman, K. M., Ling, C., Reimund, M., Graziano, G., Sampson, M. L., Playford, M. P., Dey, A. K., Reddy, A. S., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.159577 · Cited by 20
“Moreover, our observations are supported by the previous results finding that ApoC-III mainly increases plasma TGs by inhibition of lipoprotein uptake by LDL receptors (38, 39), Figure 1.”
ResultSystemic LSD1 Inhibition Prevents Aberrant Remodeling of Metabolism in Obesity
Ramms, B., Pollow, D. P., Zhu, H., Nora, C., Harrington, A. R., Omar, I., Gordts, P. L. S. M., Wortham, M., & Sander, M. (2022) · Diabetes · doi:10.2337/db21-1131 · Cited by 21
Self-citationHDL-based therapeutics: A promising frontier in combating viral and bacterial infections
Rani, A., Stadler, J. T., & Marsche, G. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108684 · Cited by 22
APOC3 Protein Is Not a Predisposing Factor for Fat-induced Nonalcoholic Fatty Liver Disease in Mice
Cheng, X., Yamauchi, J., Lee, S., Zhang, T., Gong, Z., Muzumdar, R. H., Qu, S., & Dong, H. H. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.765917 · Cited by 21
“APOC3 functions as an inhibitor of lipoprotein lipase (LPL) and hepatic lipase (HL), key enzymes responsible for the hydrolysis of TG in VLDL and chylomicrons in the post-absorption phase (12–14).”
BackgroundInfluentialApolipoprotein CIII and diabetes. Is there a link?
Christopoulou, E. C., Tsimihodimos, V., Filippatos, T. D., & Elisaf, M. (2018) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.3118 · Cited by 21
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“This could allow the lipoproteins with an affinity for these receptors, such as apoA-I and apoE, to readily bind to them (51, 52).”
BackgroundPCSK9 Activity Is Potentiated Through HDL Binding
Burnap, S. A., Sattler, K., Pechlaner, R., Duregotti, E., Lu, R., Theofilatos, K., Takov, K., Heusch, G., Tsimikas, S., Fernandez-Hernando, C. F., et al. (2021) · Circulation Research · doi:10.1161/circresaha.121.319272 · Cited by 20
Medical management of hypertriglyceridemia in pancreatitis
Gligorijevic, N., Stefanović-Račić, M., & Kershaw, E. E. (2023) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000956 · Cited by 20
“APOC3 inhibits LPL activity and promotes hepatic clearance of VLDL and chylomicrons [58,59].”
BackgroundLipid-modifying therapy in chronic kidney disease: Pathophysiological and clinical considerations
Heine, G. H., Eller, K., Stadler, J. T., Rogacev, K. S., & Marsche, G. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107459 · Cited by 19
ApoB48-remnant lipoproteins are associated with increased cardiometabolic risk in adolescents
Krysa, J. A., Vine, D. F., Beilin, L. J., Burrows, S., Huang, R., Mori, T. A., & Proctor, S. D. (2020) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2020.04.021 · Cited by 19
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“The lack of such clearance of lipoproteins remnants was found to be related to interference with the binding of ApoB/ApoE receptors via high expression of ApoC-III [32,33].”
BackgroundFamilial chylomicronemia syndrome and treatments to target hepatic APOC3 mRNA
Brinton, E. A., Eckel, R. H., Gaudet, D., Ballantyne, C. M., Baker, B. F., Ginsberg, H. N., & Witztum, J. L. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2025.119114 · Cited by 21
Self-citationWitt, C. R., Renfroe, L. G., & Lyons, S. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16335 · Cited by 18
“49 This defective catabolism of TRLs contributes more to elevated plasma TAG than their increased production.”
Lowering apolipoprotein CIII protects against high-fat diet–induced metabolic derangements
Valladolid‐Acebes, I., Åvall, K., Recio-López, P., Moruzzi, N., Bryzgalova, G., Björnholm, M., Krook, A., Fauste, E., Ericsson, M., Landfors, F., et al. (2021) · Science Advances · doi:10.1126/sciadv.abc2931 · Cited by 18
“Receptormediated hepatic clearance of lipoprotein particles has been demonstrated to be enhanced by decreasing apoCIII (5, 35, 36).”
BackgroundSoto, L. G. D. L. P., Gutierrez-Uribe, J. A., Sharma, A. K., & Ramírez‐Jiménez, A. K. (2021) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2021.09.035 · Cited by 19
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“Apolipoprotein C-III (apoC-III) is a glycoprotein secreted by the intestine and liver that binds to triglyceride-rich lipoproteins (TRLs), such as chylomicrons, very-low-density lipoprotein (VLDL), and their remnants [1, 2].”
BackgroundTriglyceride-Rich Lipoproteins
Kockx, M., & Kritharides, L. (2018) · Cardiology Clinics · doi:10.1016/j.ccl.2017.12.008 · Cited by 20
Chapman, M. J., Orsoni, A., Robillard, P., Thérond, P., & Giral, P. (2018) · Journal of clinical lipidology · doi:10.1016/j.jacl.2018.02.001 · Cited by 18
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Macromolecular Interactions of Lipoprotein Lipase (LPL)
Wheless, A., Gunn, K. H., & Neher, S. B. (2024) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-3-031-58843-3_8 · Cited by 19
Time-Restricted Feeding Reduces Atherosclerosis in LDLR KO Mice but Not in ApoE Knockout Mice
Chaix, A., Lin, T. C., Ramms, B., Cutler, R. G., Le, T., Lopez, C., Miu, P., Pinto, A. F. M., Saghatelian, A., Playford, M. P., et al. (2024) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.124.320998 · Cited by 18
Self-citationApolipoprotein CIII Is an Important Piece in the Type-1 Diabetes Jigsaw Puzzle
Valladolid‐Acebes, I., Berggren, P., & Juntti‐Berggren, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22020932 · Cited by 16
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HDL-associated apoCIII plays an independent role in predicting postprandial hypertriglyceridemia
Zhang, T., Tang, X., Mao, L., Chen, J., Kuang, J., Guo, X., Xu, D., Peng, D., & Yu, B. (2020) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2020.02.004 · Cited by 17
Sivakumar, P., Saul, M. E., Robinson, D., King, L. E., & Amin, N. B. (2024) · Scientific Reports · doi:10.1038/s41598-024-67843-8 · Cited by 17
Takenouchi, A., Tsuboi, A., Kitaoka, K., Minato, S., Kurata, M., Fukuo, K., & Kazumi, T. (2017) · Journal of Clinical Medicine Research · doi:10.14740/jocmr2871w · Cited by 16
“Very recently, Gordts et al [22] have shown fasting TG levels to be affected through a mechanism that is dependent on LDLR and LDLR-related protein 1 (LRP1) in mice.”
BackgroundJørgensen, S. F., Macpherson, M. E., Skarpengland, T., Berge, R. K., Fevang, B., Halvorsen, B. L., & Aukrust, P. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1199727 · Cited by 17
“Moreover, the VLDL-associated lipoprotein ApoC-III has emerged as being particularly important as a regulator of TG transport involving mechanisms like impairment of LPLmediated lipolysis, promotion of hepatic VLDL secretion, and suppression of TG clearance through the LDL receptor (67), and notably, ApoC-III may in i…”
BackgroundTriglyceride Treatment in the Age of Cholesterol Reduction
Agrawal, N., Corradi, P. F., Gumaste, N., & Goldberg, I. J. (2016) · Progress in Cardiovascular Diseases · doi:10.1016/j.pcad.2016.08.003 · Cited by 15
Self-citationAnower-E-Khuda, F., Singh, G., Deng, Y., Gordts, P. L. S. M., & Esko, J. D. (2019) · Glycobiology · doi:10.1093/glycob/cwz037 · Cited by 14
“The chylomicrons undergo partial lipolysis in the circulation, yielding 3H-labeled remnant particles in the circulation, which can be readily isolated by buoyant density ultracentrifugation (Gordts et al. 2016).”
BackgroundMethodInfluentialSelf-citationMarmontel, O., Filippo, M. D., Marçais, C., Nony, S., Dumoux, M., Dancer, M. S., Caussy, C., Charrière, S., & Moulin, P. (2017) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2017.07.030 · Cited by 15
Yamazaki, A., Ohkawa, R., Yamagata, Y., Horiuchi, Y., Lai, S.-J., Kameda, T., Ichimura, N., Tohda, S., & Tozuka, M. (2020) · Biological Chemistry · doi:10.1515/hsz-2020-0288 · Cited by 14
“2014), and recent studies demonstrated that apoC-III also plays a role in plasma TG increment through an LPL-independent pathway (Gaudet et al. 2014; Gordts et al. 2016).”
BackgroundKey differences between apoC-III regulation and expression in intestine and liver
West, G., Rodia, C. N., Li, D., Johnson, Z. K., Dong, H., & Kohan, A. B. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.07.116 · Cited by 17
Florentin, M., Kostapanos, M. S., Anagnostis, P. G., & Liamis, G. L. (2019) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2019.1691523 · Cited by 14
“Taking into consideration that patients with the FCS lack functional LPL activity, the aforementioned reductions should be ascribed to LPL-independent mechanisms, probably mediated by the LDL receptor or LDL receptor-related protein 1 (LRP1) [41].”
BackgroundReversal of hypertriglyceridemia in diabetic BTBR ob/ob mice does not prevent nephropathy
Attie, A., Schueler, K., Keller, M. P., Mitok, K. A., Simonett, S. P., Hudkins, K. L., Mehrotra, K., Graham, M. J., Lee, R. G., & Alpers, C. E. (2021) · Laboratory Investigation · doi:10.1038/s41374-021-00592-8 · Cited by 14
“It was previously thought that the primary mechanism of action of Apo-CIII is to inhibit LpL, but recent evidence indicates that its primary mechanism of action is by blocking VLDL interactions with the LDL receptor and the LDL receptor related protein-1 [37].”
BackgroundSelf-citationAnti-apoC-III Therapies and Implications for Treatment of Pancreatitis and Cardiovascular Disease
Tsimikas, S. (2025) · Current Atherosclerosis Reports · doi:10.1007/s11883-025-01345-4 · Cited by 16
“ApoC-III inhibits lipoprotein lipase (LPL) [15] and hepatic lipase, and delays clearance of TRLs playing a central role in the metabolism of TRLs [ 16 ].”
Xiao, Q., Wang, J., Wang, L., & Ding, H. (2024) · Biomedicines · doi:10.3390/biomedicines12061224 · Cited by 14
“In addition, APOC3 displaces APOE from TRL or directly inhibits the binding of APOE to LDLR and LDLR-related protein 1 (LRP1) on the liver surface, thereby inhibiting the hepatic clearance of TRLs [56].”
BackgroundMarston, N. A., Bergmark, B. A., Alexander, V. J., Karwatowska‐Prokopczuk, E., Kang, Y. M., Moura, F. A., Prohaska, T. A., Zimerman, A., Zhang, S. M., Murphy, S. A., et al. (2025) · American Heart Journal · doi:10.1016/j.ahj.2025.03.003 · Cited by 13
Ren, Z., Zhou, J., Yang, D., Guo, Y., Zhang, J., Xu, J., & Chen, Y. E. (2026) · Cells · doi:10.3390/cells15020134 · Cited by 13
“Other clinical testing of siRNA drugs includes RBD-5044 [166] and RN0361 [162], both in Phase II.”
Yang, X., Weber, A. A., Mennillo, E., Secrest, P., Chang, M. W., Wong, S., Le, S., Liu, J., Benner, C. W., Karin, M., et al. (2023) · Environmental Health Perspectives · doi:10.1289/ehp12381 · Cited by 12
Self-citationTsimikas, S., Ginsberg, H. N., Alexander, V. J., Karwatowska‐Prokopczuk, E., Dibble, A., Li, L., Witztum, J. L., & Hegele, R. A. (2024) · Journal of clinical lipidology · doi:10.1016/j.jacl.2024.12.018 · Cited by 12
Self-citationLipoprotein size is a main determinant for the rate of hydrolysis by exogenous LPL in human plasma
Kovrov, O., Landfors, F., Saar-Kovrov, V., Näslund, U., & Olivecrona, G. (2021) · Journal of Lipid Research · doi:10.1016/j.jlr.2021.100144 · Cited by 12
“ApoC3 demonstrate that LPL-independent inhibition of receptor-mediated uptake of lipoproteins and remnants may be more important than previously thought (14).”
BackgroundResultvan Capelleveen, J. C., Lee, S. R., Verbeek, R., Kastelein, J. J. P., Wareham, N. J., Stroes, E. S. G., Hovingh, G. K., Khaw, K., Boekholdt, S. M., Witztum, J. L., et al. (2018) · Journal of clinical lipidology · doi:10.1016/j.jacl.2018.08.010 · Cited by 12
Self-citationThe Future of Lipid-Lowering Therapy
Zwol, W. H.-V., Rimbert, A., & Kuivenhoven, J. A. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8071085 · Cited by 12
Jiang, S., Ren, Z., Yang, Y., Liu, Q., Zhou, S., & Xiao, Y. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115874 · Cited by 13
Cervantes, J., Koška, J., Kramer, F., Akilesh, S., Alpers, C. E., Mullick, A. E., Reaven, P. D., & Kanter, J. E. (2024) · JCI Insight · doi:10.1172/jci.insight.177268 · Cited by 13
“Both male and female mice were used in this study (see Supplemental Tables 1, 2, and 5–7).”
Self-citationKim, K., Yu, J., Kang, J. K., Morrow, J. P., & Pajvani, U. B. (2020) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2020.04.157 · Cited by 11
“We recently identified that GSI treatment in mice lowered plasma triglyceride-rich lipoproteins (TRLs) by increasing hepatocyte LDL-receptor (LDLR) stability [23], consistent with a role of LDLR in TRL clearance, but LDLR is well documented to regulate LDL-C uptake [24,25] and thus propensity to atherosclerosis [26].”
BackgroundLightbourne, M., Wolska, A. T., Abel, B. S., Rother, K. I., Walter, M. F., Kushchayeva, Y. S., Auh, S., Shamburek, R. D., Remaley, A. T., Muniyappa, R., et al. (2020) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaa191 · Cited by 11
“ApoC-III also has LPL-independent effects to increase triglycerides [31, 40], including inhibition of TRLP remnant uptake [32, 41, 42].”
BackgroundLipoprotein sialylation in atherosclerosis: Lessons from mice
Yu, L., Peng, J., & Mineo, C. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.953165 · Cited by 12
Novel regulators of plasma lipid levels
Loaiza, N., Oldoni, F., & Kuivenhoven, J. A. (2017) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000416 · Cited by 10
In the Beginning, Lipoproteins Cross the Endothelial Barrier
Goldberg, I. J., Cabodevilla, A. G., & Younis, W. (2024) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv22017 · Cited by 10
Self-citationLi, J., Sun, H., Wang, Y., Liu, J., & Wang, G. (2023) · Lipids in Health and Disease · doi:10.1186/s12944-023-01797-0 · Cited by 9
“In addition, ApoC3 could inhibit TRL lipoprotein clearance by the liver [26, 27].”
BackgroundPostprandial Hyperchylomicronemia and Thin-Cap Fibroatheroma in Nonculprit Lesions
Kurihara, O., Okajima, F., Takano, M., Kato, K., Munakata, R., Murakami, D., Miyauchi, Y., Emoto, N., Sugihara, H., Seino, Y., et al. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.311245 · Cited by 9
Chen, R. K., Petrazzini, B. O., Duffy, Á., Rocheleau, G., Jordan, D. M., Bansal, M. B., & Do, R. (2025) · Genome biology · doi:10.1186/s13059-025-03518-5 · Cited by 10
Discovery of long-acting APOC3 siRNA for treating patients with hypertriglyceridemia
Prakash, T. P., Mullick, A. E., Riney, S., Yu, J., Nikan, M., Quirk, C., Crutchfield, A., Damle, S. S., Klein, S., & Swayze, E. E. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf1063 · Cited by 8
“Mechanistic studies have demonstrated that elevated plasma apoC3 impacts plasma triglyceride metabolism by two distinct mechanisms: inhibition of lipoprotein lipase (LPL) and reduced hepatocyte uptake of triglyceride-rich lipoproteins (TRL) [ 29 , 30 ].”
Self-citationUncovering the role of apolipoprotein C-III in insulin resistance
Aguilar-Recarte, D., Palomer, X., & Vázquez‐Carrera, M. (2020) · Clínica e Investigación en Arteriosclerosis · doi:10.1016/j.arteri.2020.09.003 · Cited by 8
A New Treatment Strategy for Diabetic Dyslipidemia?
Kothari, V. M., & Bornfeldt, K. (2020) · Diabetes · doi:10.2337/dbi20-0035 · Cited by 8
Akram, M. A., Khodja, A., Dalibalta, S., & Majdalawieh, A. F. (2025) · Current Medicinal Chemistry · doi:10.2174/0109298673348217241119063941 · Cited by 8
Yang, X., Alexander, V. J., Xia, S., & Tsimikas, S. (2025) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2025.120462 · Cited by 7
Increasing the complexity of lipoprotein characterization for cardiovascular risk in type 2 diabetes
Guardiola, M., Rehues, P., Amigó, N., Arrieta, F., Botana, M., Gimeno-Orna, J. A., Girona, J., Martínez‐Montoro, J. I., Ortega, E., Pérez, A., et al. (2024) · European Journal of Clinical Investigation · doi:10.1111/eci.14214 · Cited by 7
“…ASCVD; for example, apoC-III inhibits lipoprotein lipase; inhibits the apoE-mediated uptake of lipoproteins by the liver receptors LDLR and LRP1 58 ; induces the aggregation of LDL particles and their binding to proteoglycans 59 ; or triggers inflammation by inducing the expression of adhesion…”
Palmisano, B. T., Yu, S., Neuman, J. C., Zhu, L., Luu, T. N., & Stafford, J. M. (2021) · Physiological Reports · doi:10.14814/phy2.14732 · Cited by 7
“Additionally, several studies demonstrate that dyslipidemia can be improved in the setting of LDLR knockout (Gordts et al., 2016; Saraswathi et al., 2007).”
BackgroundTillo, M., Lamanna, W. C., Dwyer, C. A., Sandoval, D. R., Pessentheiner, A. R., Al-Azzam, N., Sarrazin, S., Gonzales, J. C., Kan, S., Andreyev, A. Y., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102159 · Cited by 7
“Postprandial lipid accumulation in organs was evaluated as described (44).”
BackgroundSelf-citationDatta, R., Gholampour, M. A., Yang, C. D., Volk, R. F., Lin, S., Podolsky, M. J., Arnold, T., Rieder, F., Zaro, B. W., Verzi, M. P., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112249 · Cited by 7
“5 mg/g body weight of mice) 1 hour before the oral gavage (47).”
BackgroundNovel Hypolipidaemic Drugs: Mechanisms of Action and Main Metabolic Effects
Filippatos, T. D., Liontos, A., Christopoulou, E. C., & Elisaf, M. (2018) · Current Vascular Pharmacology · doi:10.2174/1570161116666180209112351 · Cited by 7
Gene Delivery in Lipid Research and Therapies
Giorgi, M. D., & Lagor, W. R. (2019) · Methodist DeBakey Cardiovascular Journal · doi:10.14797/mdcj-15-1-62 · Cited by 7
Yoon, H., Lee, Y., Kang, H., Ju, J., Ji, Y., Park, H., Park, H., Lee, H. J., & Holzapfel, W. H. (2021) · Journal of Applied Microbiology · doi:10.1111/jam.15181 · Cited by 8
Wang, Y. E., Kirschke, C. P., Woodhouse, L. R., Bonnel, E. L., Stephensen, C. B., Bennett, B. J., Newman, J. W. I., Keim, N. L., & Huang, L. (2022) · BMC Nutrition · doi:10.1186/s40795-022-00592-x · Cited by 9
“Importantly, ApoC3 can significantly reduce LDL clearance rate by inhibiting the receptormediated LDL endocytosis in the liver [16].”
BackgroundDedousis, N. L., Teng, L., Kanshana, J. S., & Kohan, A. B. (2022) · Journal of Lipid Research · doi:10.1016/j.jlr.2022.100284 · Cited by 7
“endocytosis (38), respectively, and apoC-II stimulates”
Genetic Assessment and Clinical Correlates in Severe Hypertriglyceridemia: A Systematic Review
Luca, C. D., Ciciola, P., D’Errico, G., Taranto, M. D. D., Fortunato, G., Gross, C., Garn, J., Iannuzzo, G., Minno, M. N. D. D., & Calcaterra, I. L. (2025) · Genes · doi:10.3390/genes16111377 · Cited by 7
“Functionally, ApoCIII inhibits lipoprotein lipase (LPL) activity and impairs the hepatic clearance of TRL remnants via blockade of lipoprotein receptors, underscoring its role in multiple steps of triglyceride metabolism [17].”
Toth, P. P., & Banach, M. (2025) · Archives of Medical Science · doi:10.5114/aoms/216960 · Cited by 7
“…lipoproteins by two mechanisms: (1) it displaces apoE, which impairs binding of the lipoprotein to a lipoprotein receptor, and (2) it downregulates the expression of the low-density lipoprotein receptor (LDL-R) and LDL-like receptor related protein (LDL-RP) along the hepatocyte surface [37].”
Advances in diagnosis and potential therapeutic options for familial chylomicronemia syndrome
Benes, L. B., Brandt, E. J., & Davidson, M. H. (2017) · Expert Opinion on Orphan Drugs · doi:10.1080/21678707.2018.1419863 · Cited by 6
“Apolipoprotein C3 inhibits hepatic receptor-mediated uptake of TRL [60], primarily via hepatic heparin sulfate proteoglycan receptors and LDL receptors [61].”
BackgroundLife is complicated: so is apoCIII
Reyes‐Soffer, G., & Ginsberg, H. N. (2019) · Journal of Lipid Research · doi:10.1194/jlr.c119000214 · Cited by 6
“In this issue of the Journal of Lipid Research, Ramms and colleagues extend their previous studies that dissected the hepatic pathways involved in apoCIII-mediated inhibition of TGRL uptake in mice (17) by focusing on the impact of apoE on apoCIII’s effects on the latter pathway and on LPL-mediated hydrolysis of TG in…”
BackgroundTreatment of the metabolic syndrome by siRNA targeting apolipoprotein CIII
Recio-López, P., Valladolid‐Acebes, I., Hadwiger, P., Hoßbach, M., Krampert, M., Prata, C. A. H., Berggren, P., & Juntti‐Berggren, L. (2022) · BioFactors · doi:10.1002/biof.1885 · Cited by 6
Kim, D. H., Lee, S., Noh, S. G., Lee, J., & Chung, H. Y. (2024) · Aging · doi:10.18632/aging.205610 · Cited by 6
The Potential of RNA Therapeutics in Treating Cardiovascular Disease
Mainkar, G., Ghiringhelli, M., & Zangi, L. (2025) · Drugs · doi:10.1007/s40265-025-02173-1 · Cited by 6
“APOC3 plays a role in suppressing triglyceride clearance, and multiple studies have shown that downregulation of APOC3 expression leads to reduced levels of circulating triglycerides and protection against CVD in both mice and humans [133–137].”
Apolipoproteins in circulation: At the interface of thrombosis and stroke initiation
Etuzé, T., Vivien, D., & Dubois, F. (2025) · Progress in Lipid Research · doi:10.1016/j.plipres.2025.101343 · Cited by 6
Cabodevilla, A. G., Izquierdo, M. C., Basu, D., Younis, W., Tirumalasetty, M. B., Miao, Q. R., Nasias, D., Kanter, J. E., Ho, T. W. W., Gjini, J., et al. (2026) · Nature Communications · doi:10.1038/s41467-025-68193-3 · Cited by 5
“…for fi ve consecutive days. i Lpl − / − mice analyzed 3 weeks after the last tamoxifen injection show an approximately 95% reduction in LpL gene expression and an 80 – 90% decrease in LpL activity in heart, skeletal muscle, and white adipose tissue, and a >90% reduction in plasma LpL activity 27 .”
Self-citationRehues, P., Girona, J., Guardiola, M., Ozcariz, E., Amigó, N., Rosales, R., Esteban, Y., Banús, H., Alsina, G. G., González-Lleó, A. M., et al. (2024) · Cardiovascular Diabetology · doi:10.1186/s12933-024-02531-5 · Cited by 6
The Essence of Lipoproteins in Cardiovascular Health and Diseases Treated by Photodynamic Therapy
Wańczura, P. M., Aebisher, D., Iwański, M. A., Myśliwiec, A., Dynarowicz, K., & Bartusik‐Aebisher, D. (2024) · Biomedicines · doi:10.3390/biomedicines12050961 · Cited by 5
Recent explanatory trials of the mode of action of drug therapies on lipoprotein metabolism
Chan, D. C., Barrett, P. H. R., & Watts, G. F. (2016) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000348 · Cited by 5
“Recent experiment data suggest that apoC-III ASO lowers plasma triglycerides by increasing hepatic TRL clearance via the LDL receptor and LDL receptor-related protein-1 pathway [48].”
BackgroundBando, H., Taneda, S., & Manda, N. (2021) · JMA Journal · doi:10.31662/jmaj.2020-0104 · Cited by 5
“In addition, Apo CII, Apo CIII, and Apo E play important roles in the metabolism and clearance of TG-rich lipoproteins (14), (15), ((16)).”
BackgroundDeep Apolipoprotein Proteomics to Uncover Mechanisms of Coronary Disease Risk ∗
Rader, D. J., Bajaj, A., & Khetarpal, S. A. (2017) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2016.11.066 · Cited by 5
“suggested by the demonstrated efficacy of volanesorsen in TG reduction, even in patients with inherited LPL deficiency (17), and recent murine studies of the APOC3 ASO comparing effects in LPLexpressing versus deficient models (21).”
BackgroundGinsberg, H. N., & Bornfeldt, K. (2026) · Circulation Research · doi:10.1161/circresaha.125.327267 · Cited by 4
“BMI indicates body mass index; BP, blood pressure; CAC, coronary artery calcium; FFA, free fatty acid; FG, fasting glucose; GPIHBP1, glycosylphosphatidylinositol-anchored-HDL-binding protein 1; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LMF1, lipase maturation factor 1; LP…”
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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