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

P. Barton Duell

doi:10.53941/ijctm.2025.100008

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.

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