Figure 6.

ApoCIII: a major inhibitor of LPL activity with physiological and pharmacological importance. (1). Hepatocytes have the apoCIII gene for a protein of about 8 kilodaltons. Its regulation is complex but can be summarized as follows: (2) The two main inhibitors are insulin and polyunsaturated fatty acids, whereas (3) the main enhancers are glucose, fructose, and saturated fatty acids. (4) In this regard, insulin resistance (IR) negates the inhibition promoting increased expression of an ApoCIII delayed catabolism of TRLs, as seen in metabolic syndrome and diabetes, and at the same time produces hyperglycemia, which directly stimulates the production. Diets very rich in sugar or saturated fat enhance the production of apo CIII. (5) ApoCIII is a small protein that gets glycosylated in the Golgi apparatus and circulates in three isoforms with 0, 1 (most abundant), or 2 sialic acid residues. Isoform distribution may have a bearing in the final activity of the protein. (6) ApoCIII in VLDL and chylomicrons (which get it by transfer from VLDL or from HDL) potently inhibits lipoprotein lipase activity and acts as a counterpart of the main activator, which is ApoCII. Other key inhibitors are apoAV, ANGPTL3-4 and 8, as we show later. (7) Excess activity of apoCIII result in increased residence time of VLDLs and chylomicron remnants. (8) As indicated earlier, remnants are taken up by several receptor mechanisms in the liver. ApoCIII also inhibits this reuptake, especially in rodents. The activity in humans has lately been regarded as less important when compared to its action on LPL. The key role of apoCIII in this process as well as results from animal and human loss of function studies have uncovered the potential role of apoCIII inhibitors as a therapeutic avenue for hypertriglyceridemia, as we further discuss in this review. The figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.