Exploring apolipoprotein C-III: pathophysiological and pharmacological relevance

The availability of pharmacological approaches able to effectively reduce circulating LDL cholesterol (LDL-C) has led to a substantial reduction in the risk of atherosclerosis-related cardiovascular disease (CVD). However, a residual cardiovascular (CV) risk persists in treated individuals with optimal levels of LDL-C. Additional risk factors beyond LDL-C are involved, and among these, elevated levels of triglycerides (TGs) and TG-rich lipoproteins are causally associated with an increased CV risk. Apolipoprotein C-III (apoC-III) is a key regulator of TG metabolism and hence circulating levels through several mechanisms including the inhibition of lipoprotein lipase activity and alterations in the affinity of apoC-III-containing lipoproteins for both the hepatic receptors involved in their removal and extracellular matrix in the arterial wall. Genetic studies have clarified the role of apoC-III in humans, establishing a causal link with CVD and showing that loss-of-function mutations in the APOC3 gene are associated with reduced TG levels and reduced risk of coronary heart disease. Currently available hypolipidaemic drugs can reduce TG levels, although to a limited extent. Substantial reductions in TG levels can be obtained with new drugs that target specifically apoC-III; these include two antisense oligonucleotides, one small interfering RNA and an antibody. Graphical Abstract The enrichment in apolipoprotein C-III (apoC-III) content impairs the hepatic clearance of triglyceride-rich lipoprotein remnants and may contribute to the formation of atherosclerotic plaque. Several options targeting specifically apoC-III are under development, including antisense oligonucleotides (volanesorsen and olezarsen), a siRNA (ARO-APOC3) and an antibody (STT-5058).

Automated summary

Pharmacological approaches for reducing LDL cholesterol have been effective in reducing cardiovascular disease risk, but residual risk persists. Elevated triglycerides and triglyceride-rich lipoproteins are associated with increased cardiovascular risk, and apoC-III plays a key role in regulating their metabolism. New drugs targeting apoC-III can substantially reduce triglyceride levels.