Apolipoprotein C-III and Pathophysiology of Severe Hypertriglyceridemia: A New Frontier in Therapeutic Intervention

Abstract

Apolipoprotein C-III (apo C-III) is an important regulator of metabolism of triglyceride-rich lipoproteins that include hepatically-derived very low-density lipoproteins, intestinally derived chylomicrons, and remnant lipoproteins. Apo C-III is carried on triglyceride-rich lipoproteins, but exchanges bidirectionally with high-density lipoprotein particles. Apo C-III inhibits lipoprotein lipase (LPL), a key mediator of clearance of triglycerides from plasma, thereby contributing to hypertriglyceridemia. Apo C-III is also involved in hepatic VLDL synthesis and secretion, interferes with apo E-mediated clearance of triglyceride-rich lipoproteins, has proinflammatory properties, and has a causative role in development of atherosclerotic cardiovascular disease. Familial chylomicronemia syndrome (FCS) is a rare recessive condition caused by defects in LPL, or four associated proteins, and is associated with severe hypertriglyceridemia and recurrent pancreatitis. Standard triglyceride-lowering interventions lack efficacy in patients with FCS, so there has been a quest to develop efficacious and safe medications for treatment of FCS. In December 2024, olezarsen, an antisense oligonucleotide medication targeting apo C-III, was FDA approved for treatment of patients with FCS. It substantially lowered levels of apo C-III and triglycerides in plasma and reduced the incidence of pancreatitis by 88%. Plozasiran, an experimental small interfering RNA compound targeting apo C-III that may be approved in late 2025, also substantially lowered levels of apo C-III and triglycerides in plasma and reduced pancreatitis risk by 83%. The availability of olezarsen, and possible availability of plozasiran later this year, has ushered in a new era of highly efficacious treatments for FCS that can prevent pancreatitis and improve quality of life.

Keywords

apolipoprotein C-III / apo C-III / hypertriglyceridemia / familial chylomicronemia syndrome (FCS) / olezarsen / plozasiran

References

[1] Brown, W.V.; Levy, R.I.; Fredrickson, D.S. Studies of the proteins in human plasma very low-density lipoproteins. J. Biol. Chem. 1969, 244, 5687-5694.

[2] Brown, W.V.; Baginsky, M.L. Inhibition of lipoprotein lipase by an apoprotein of human very low-density lipoprotein. Biochem. Biophys. Res. Commun. 1972, 46, 375-382.

[3] Packard, C.J.; Pirillo, A.; Tsimikas, S.; et al. Exploring apolipoprotein C-III: Pathophysiological and pharmacological relevance. Cardiovasc. Res. 2024, 119, 2843-2857.

[4] Taskinen, M.R.; Borén, J. Why is apolipoprotein C-III emerging as a novel therapeutic target to reduce the burden of cardiovascular disease? Curr. Atheroscler. Rep. 2016, 18, 59.

[5] Fredenrich, A.; Giroux, L.M.; Tremblay, M.; et al. Plasma lipoprotein distribution of apo C-III in normolipidemic and hypertriglyceridemic subjects: Comparison of the apo C-III to apo E ratio in different lipoprotein fractions. J. Lipid Res. 1997, 38, 1421-1432.

[6] Yamazaki, A.; Ohkawa, R.; Yamagata, Y.; et al. Apolipoprotein C-II and C-III preferably transfer to both high-density lipoprotein (HDL)2 and the larger HDL3 from very low-density lipoprotein (VLDL). Biol. Chem. 2021, 402, 439-449.

[7] Ginsberg, H.N.; Packard, C.J.; Chapman, M.J.; et al. Triglyceride-rich lipoproteins and their remnants: Metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur. Heart J. 2021, 42, 4791-4806.

[8] Do, R.; Willer, C.J.; Schmidt, E.M.; et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 2013, 45, 1345-1352.

[9] Nordestgaard, B.G. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: New insights from epidemiology, genetics, and biology. Circ. Res. 2016, 118, 547-563.

[10] Jorgensen, A.B.; Frikke-Schmidt, R.; Nordestgaard, B.G.; et al. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 2014, 371, 32-41.

[11] The TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 2014, 371, 22-31.

[12] Sinari, S.; Koska, J.; Hu, Y.; et al. Apo CIII Proteoforms, Plasma Lipids, and Cardiovascular Risk in MESA. Arterioscler. Thromb. Vasc. Biol. 2023, 43, 1560-1571.

[13] Baass, A.; Paquette, M.; Bernard, S.; et al. Familial chylomicronemia syndrome: An under-recognized cause of severe hypertriglyceridaemia. J. Intern. Med. 2020, 287, 340-348.

[14] Rosenson, R.S.; Gaudet, D.; Ballantyne, C.M.; et al. Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: A phase 2 randomized trial. Nat. Med. 2023, 29, 729-737.

[15] Witztum, J.L.; Gaudet, D.; Freedman, S.D.; et al. Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome. N. Engl. J. Med. 2019, 381, 531-542.

[16] Stroes, E.S.G.; Alexander, V.J.; Karwatowska-Prokoczuk, E.; et al. Olezarsen, acute pancreatitis, and familial chylomicronemia syndrome. N. Engl. J. Med. 2024, 390, 1781-1792.

[17] Watts, G.F.; Rosenson, R.S.; Hegele, R.A.; et al. Plozasiran for managing persistent chylomicronemia and pancreatitis risk. N. Engl. J. Med. 2025, 392, 127-137.

[18] Gaudet, D.; Pall, D.; Watts, G.F.; et al. Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial. JAMA Cardiol. 2024, 9, 620-630.

[19] Ballantyne, C.M.; Gaudet, D.; Rosenson, R.S.; et al. Effect of Targeting apoC-III with Plozasiran on Lipoprotein Particle Size and Number in Hypertriglyceridemia. J. Am. Coll. Cardiol. 2025, in press. https://doi.org/10.1016/j.jacc.2025.03.496.

[20] Karwatowska-Prokopczuk, E.; Tardif, J.C.; Gaudet, D.; et al. Effect of olezarsen targeting APOC-III on lipoprotein size and particle number measured by NMR in patients with hypertriglyceridemia. J. Clin. Lipidol. 2022, 16, 617-625.