Exploring apolipoprotein C-III: Pathophysiological and pharmacological relevance.

The availability of pharmacological approaches able to effectively reduce circulating low-density lipoprotein cholesterol (LDL-C) has led to a substantial reduction in the risk of atherosclerosis-related cardiovascular disease. However, a residual cardiovascular 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 (TG) and triglyceride-rich lipoproteins are causally associated with an increased cardiovascular 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 (LPL) 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 cardiovascular disease, 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 hypolipidemic 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.