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Apoliprotein C-III (Apo C-III) inhibitors effect of antisense oligonucleotides in the management of dyslipidemia


Introduction: Dyslipidemia is an abnormal condition of blood lipid levels with a global prevalence of 31.2% which can cause various complications including atherosclerosis that can develop into stroke. Therefore, it is necessary to develop therapeutic modalities. One of them is Antisense Oligonucleotides (ASO) which target Apo C-III, a protein that controls body fat metabolism.

Purpose: This study aims to summarize the current progress, challenges, and potency of the apoliprotein C-III (Apo C-III) inhibitors effect of antisense oligonucleotides in the management of dyslipidemia

Methods: This paper is a literature review that collects and selects data from credible sources using the keywords apoliprotein C-III, antisense oligonucleotides, and dyslipidemia

Results: Antisense Oligonucleotides have high specificity and efficiency in inhibiting Apo C-III. Administration of ASO significantly reduced Apo C-III mRNA up to 98% and Apo C-III plasma protein up to 65% in experimental animals and reduced triglycerides up to 70.9% in clinical trials. A decrease in very low density lipoprotein (VLDL) of up to 69.2% was identified in the administration of ISIS 304801, spesific ASO in humans. The administration of ISIS 304801 also reduced the number of chylomicron particles as a source of cholesterol up to 61.1% and significantly increased the number of high-density lipoprotein (HDL) up to 45.7%, which represented the role of the modality as atheroprotection. Over time, an increase in the endosomal release, distribution, and half-life of ASO was achieved by modification of phosphorothioate linkages and lipid conjugation which represented an increase in ASO concentration. It also facilitates the interaction between ASO and intracellular spesific Apo C-III coding mRNA

Conclusion: Antisense oligonucleotides have great potential to inhibit Apo C-III as a treatment for dyslipidemia.



  1. Schmitz J G-BI. Apo C-III Antisense Oligonucleotides: A New Option for the Treatment of Hypertriglyceridemia. Curr Med Chem. 2018;25(13):1567–76.
  2. Xi Y NLCNBHXXZH. Prevalence of dyslipidemia and associated risk factors among adults aged ≥35 years in northern China: A cross-sectional study. BMC Public Health. 2020;20(1):1–9.
  3. Huang Y GLXXTS. Epidemiology of dyslipidemia in Chinese adults: meta-analysis of prevalence, awareness, treatment, and control. Popul Heal Metr. 2014;12(1).
  4. E E SAPJTPSRRS. Pedoman Tatalaksana Dislipidemia PERKI 2013. Indones J Cardiol. 2013;34(4):245–70.
  5. Mosca S AGCVCJBAME. Dyslipidemia Diagnosis and Treatment: Risk Stratification in Children and Adolescents. J Nutr Metab. 2022;
  6. Rinjani AM SMHL. Abnormal Blood Lipids Levels (Dyslipidemia) Treatment With Acupuncture Method. J Vocat Heal Stud. 2022;5(3):157.
  7. Mancini GBJ HRL LA. Dyslipidemia. Can J Diabetes. 2018;42:178–85.
  8. Gebreegziabiher G BTMKTD. Prevalence of dyslipidemia and associated risk factors among adult residents of Mekelle City, Northern Ethiopia. PLoS One. 2021.
  9. Nelson RH. Hyperlipidemia as a Risk Factor for Cardiovascular Disease. Prim Care - Clin Off Pract. 2013;40(1):195–211.
  10. Rachmawati C MSAK. Analisis Faktor Risiko Modifikasi Penyakit Jantung Koroner Di Rsu Haji Surabaya Tahun 2019. Media Gizi Kesmas. 2021;10(1):47.
  11. Kaur H AB. Assessing the Prevalence of Dyslipidemia in Apparently Healthy Urban Obese Adults Residing in South Delhi, India. J Gizi dan Pangan. 2020;15(2):63–70.
  12. Helkin A SJLSSSMKG V. Dyslipidemia Part 1 - Review of Lipid Metabolism and Vascular Cell Physiology. Vasc Endovasc Surg. 2016;50(2):107–18.
  13. Warraich HJ RJ. Dyslipidemia in diabetes mellitus and cardiovascular disease. Cardiovasc Endocrinol. 2017;6(1):27–32.
  14. PERKENI. Pedoman Pengelolaan Dislipidemia di Indonesia. In: Pedoman Pengelolaan Dislipidemia di Indonesia. 2019. p. 1.
  15. Borén J PCTM. The Roles of Apo C-III on the Metabolism of Triglyceride-Rich Lipoproteins in Humans. Front Endocrinol. 2020 Jul;11:1–10.
  16. Ramms B GP. Apolipoprotein C-III in triglyceride-rich lipoprotein metabolism. Curr Opin Lipidol. 2018;29(3):171–9.
  17. Yassine HN TORAPAKJWR. The association of human apolipoprotein C-III sialylation proteoforms with plasma triglycerides. PLoS One. 2015;10(12):1–14.
  18. Han SH NSSIZDKK. Hypertriglyceridemia and cardiovascular diseases: Revisited. Korean Circ J. 2016;46(2):135–44.
  19. Lamprea-Montealegre JA SNHWHREJBC et al. Apolipoprotein B, triglyceride-rich lipoproteins, and risk of cardiovascular events in persons with CKD. Clin J Am Soc Nephrol. 2020;15(1):47–60.
  20. Milonas D TK. Experimental therapies targeting apolipoprotein C-III for the treatment of hyperlipidemia–spotlight on volanesorsen. Expert Opin Investig Drugs. 2019;28(4):389–94.
  21. Taskinen MR BJ. Why Is Apolipoprotein CIII Emerging as a Novel Therapeutic Target to Reduce the Burden of Cardiovascular Disease? Curr Atheroscler Rep. 2016;18(10):1–8.
  22. Norata GD TSPAC AL. Apolipoprotein C-III: From Pathophysiology to Pharmacology. Trends Pharmacol Sci. 2015. p. 675–87.
  23. Toth PP. Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease. Vasc Heal Risk Manag. 2016;12:171–83.
  24. Luo M PD. The emerging role of apolipoprotein C-III: Beyond effects on triglyceride metabolism. Lipids Health Dis. 2016. p. 1–7.
  25. Taskinen MR PCBJ. Emerging Evidence that Apo C-III Inhibitors Provide Novel Options to Reduce the Residual CVD. Curr Atheroscler Rep. 2019;21(8).
  26. Hieronimus B GSKNBABLNK et al. Effects of fructose or glucose on circulating Apo C-III and triglyceride and cholesterol content of lipoprotein subfractions in humans. J Clin Med. 2019;8(7):1–15.
  27. Glil Alkushi A. Alternative Natural Management of Dyslipidemia. Dyslipidemia. 2019;
  28. Quiroga B RPCV. Efficacy and safety of the PCSK9 inhibitors in the treatment of dyslipidemia in chronic kidney disease. Nefrologia. 2020;40(5):499–505.
  29. Turner AP ACBR. Efflux transporters in cancer resistance: Molecular and functional characterization of P-glycoprotein. Elsevier Inc. 2020.
  30. Atri C GFLD. MicroRNAs in diagnosis and therapeutics . Elsevier Inc. 2019.
  31. Sunshine SS, Jarecki J, MacKenzie A, Chen KS. Spinal Muscular Atrophy Therapeutics Development. Spinal Muscular Atrophy: Disease Mechanisms and Therapy. Elsevier Inc.; 2017. 263–281 p.
  32. Crooke ST BBCRLX hai. Antisense technology: an overview and prospectus. Nat Rev Drug Discov. 2021;20(6):427–53.
  33. Raal FJ SRBDMACMCW et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375(9719):998–1006.
  34. Witztum JL GDFSAVDAWK et al. Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome. N Engl J Med. 2019;381(6):531–42.
  35. Gaudet D AVBBBDTKSW et al. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med. 2015;373(5):438–47.
  36. Viney NJ van CJGRXSTJYR et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016;388(10057):2239–53.
  37. Van Poelgeest EP HMMMTYLAPR et al. Antisense-mediated reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9): A first-in-human randomized, placebo-controlled trial. Br J Clin Pharmacol. 2015;80(6):1350–61.
  38. Graham MJ LRBTTL-JFWPR et al. Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides. N Engl J Med. 2017;377(3):222–32.
  39. Graham MJ LRBTFWMAAV et al. Antisense oligonucleotide inhibition of apolipoprotein c-iii reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 2013;112(11):1479–90.
  40. Kapustin AN DPLDMCLERN et al. Antisense oligonucleotide activity in tumour cells is influenced by intracellular LBPA distribution and extracellular vesicle recycling. Commun Biol. 2021;4(1):1–13.
  41. Wang S SHTMLXCS. Intra-endosomal trafficking mediated by lysobisphosphatidic acid contributes to intracellular release of phosphorothioate-modified antisense oligonucleotides. Nucleic Acids Res. 2017;45(9):5309–22.
  42. Wang S ANPTLXCS. Lipid Conjugates Enhance Endosomal Release of Antisense Oligonucleotides into Cells. Nucleic Acid Ther. 2019;29(5):245–55.
  43. Huang JK LH. Emerging Evidence of Pathological Roles of Very-Low-Density Lipoprotein (VLDL). Int J Mol Sci. 2022;23(8):1–21.
  44. Gentile M IAGFDAVEPM et al. Association between very low-density lipoprotein cholesterol (VLDL-C) and carotid intima-media thickness in postmenopausal women without overt cardiovascular disease and on LDL-C target levels. J Clin Med. 2020;9(5).
  45. Rioja J AMG-CNC-PIATM-GO et al. Evaluation of the chylomicron-TG to VLDL-TG ratio for type I hyperlipoproteinemia diagnostic. Eur J Clin Invest. 2020 May;50(12):0–3.
  46. Packard CJ BJTM. Causes and Consequences of Hypertriglyceridemia. Front Endocrinol. 2020;50(12):1–15.
  47. Rahmany S JI. Biochemistry, Chylomicron. StatPearls. 2021;
  48. Kosmas CE MISABKV. CFTV et al. High-density lipoprotein (HDL) functionality and its relevance to atherosclerotic cardiovascular disease. Drugs Context. 2018;7:1–9.
  49. Suleiman S JCVM. Quality over Quantity: A Case Based Review of HDL Function and Dysfunction. Int J Clin Cardiol. 2020;7(3):1–7.
  50. Rysz J G-BAR-GMFB. The role and function of HDL in patients with chronic kidney disease and the risk of cardiovascular disease. Int J Mol Sci. 2020;21(2).
  51. Untersteller K MSTMEIZAHM et al. HDL functionality and cardiovascular outcome among nondialysis chronic kidney disease patients. J Lipid Res. 2018;59(7):1256–65.
  52. Honda H MTKT. Degenerated HDL and Its Clinical Implications. Elsevier Inc. 2017;
  53. Gordts PL NRSNRBLIGJ et al. Apo C-III Modulates Clearance of Triglyceride-Rich Lipoproteins in Mice Through Low Density Lipoprotein Family Receptors. J Clin Invest. 2016;126(8):2855–66.
  54. Carlos O Mendivil MD DSc DsEFJDsSMF. Low Density Lipoproteins Containing Apolipoprotein C-III and the Risk of Coronary Heart Disease. Mol Cell Biochem. 2012;23(1):1–7.
  55. Kohan AB. Apolipoprotein C-III: A potent modulator of hypertriglyceridemia and cardiovascular disease. Curr Opin Endocrinol Diabetes Obes. 2015;22(2):119–25.
  56. Wan WB MMVGMHNJGH et al. Synthesis, biophysical properties and biological activity of second generation antisense oligonucleotides containing chiral phosphorothioate linkages. Nucleic Acids Res. 2014;42(22):13456–68.
  57. Crooke ST VTLX. Phosphorothioate modified oligonucleotide-protein interactions. Nucleic Acids Res. 2021;48(10):5235–53.
  58. Relizani K ELZFGCDCAP et al. Palmitic acid conjugation enhances potency of tricyclo-DNA splice switching oligonucleotides. Nucleic Acids Res. 2022;50(1):17–34.
  59. Hvam ML CYD-HFNJWJKJ et al. Fatty Acid-Modified Gapmer Antisense Oligonucleotide and Serum Albumin Constructs for Pharmacokinetic Modulation. Mol Ther. 2017;25(7):1710–7.
  60. Nurmohamed NS DGSE. Targeting Apo C-III and ANGPTL3 in the treatment of hypertriglyceridemia. Expert Rev Cardiovasc Ther. Expert Rev Cardiovasc Ther. 2020;18(6):355–61.
  61. Zhang Y HWHCWJLXZX et al. Large triglyceride-rich lipoproteins in hypertriglyceridemia are associated with the severity of acute pancreatitis in experimental mice. Cell Death Dis. 2019;10(10).
  62. Kilanowska A SS. In vivoandin vitrostudies of antisense oligonucleotides - a review. RSC Adv. 2020;10(57):34501–16.
  63. Osborn MF CABAHRRLDS et al. Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways. Nucleic Acids Res. 2019;47(3):1070–81.

How to Cite

Sasmana, I. G. A. P., Rahadi, P. N. K., Devy, A. A. T., Dewi, P. A. S., Supadmanaba, I. G. P., & Wihandani, D. M. (2023). Apoliprotein C-III (Apo C-III) inhibitors effect of antisense oligonucleotides in the management of dyslipidemia. Indonesia Journal of Biomedical Science, 17(1), 51–56.




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I Gede Aswin Parisya Sasmana
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Putu Nindya Krisnadewi Rahadi
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Anggi Amanda Triana Devy
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I Gede Putu Supadmanaba
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