Endocrinol Metab.  2022 Aug;37(4):575-586. 10.3803/EnM.2022.402.

Lipoprotein Lipase: Is It a Magic Target for the Treatment of Hypertriglyceridemia

• Moon JH
• Kim K
• Choi SH

• KMID: 2532857
• DOI: http://doi.org/10.3803/EnM.2022.402

Abstract

High levels of triglycerides (TG) and triglyceride-rich lipoproteins (TGRLs) confer a residual risk of cardiovascular disease after optimal low-density lipoprotein cholesterol (LDL-C)–lowering therapy. Consensus has been made that LDL-C is a non-arguable primary target for lipid lowering treatment, but the optimization of TGRL for reducing the remnant risk of cardiovascular diseases is urged. Omega-3 fatty acids and fibrates are used to reduce TG levels, but many patients still have high TG and TGRL levels combined with low high-density lipoprotein concentration that need to be ideally treated. Lipoprotein lipase (LPL) is a key regulator for TGs that hydrolyzes TGs to glycerol and free fatty acids in lipoprotein particles for lipid storage and consumption in peripheral organs. A deeper understanding of human genetics has enabled the identification of proteins regulating the LPL activity, which include the apolipoproteins and angiopoietin-like families. Novel therapeutic approach such as antisense oligonucleotides and monoclonal antibodies that regulate TGs have been developed in recent decades. In this article, we focus on the biology of LPL and its modulators and review recent clinical application, including genetic studies and clinical trials of novel therapeutics. Optimization of LPL activity to lower TG levels could eventually reduce incident atherosclerotic cardiovascular disease in conjunction with successful LDL-C reduction.

Keyword

Lipoprotein lipase; Triglycerides; Apolipoproteins; Cholesterol; Cardiovascular diseases; Oligonucleotides, antisense; Angiopoietin-like protein 3; PPAR alpha; Fatty acids, omega-3; Fibric acids

Figure

• 

  Fig. 1. Overview of the role of lipoprotein lipase in triglyceride metabolism. De novo lipogenesis from the liver results in the secretion of triglycerides in the form of very-low-density lipoprotein cholesterol (VLDL). Dietary fat is transported from intestine to circulation as part of chylomicrons. The triglycerides in chylomicrons and VLDL are hydrolyzed by lipoprotein lipase (LPL). Chylomicron remnants, intermediate-density lipoprotein (IDL) cholesterol, and low-density lipoprotein (LDL) cholesterol are produced as byproducts. LPL is produced from parenchymal cells, including adipose tissue and muscle. LPL is attached to the cell surface via heparan sulfate proteoglycans (HSPGs). Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) transports LPL from the cell surface to the vascular endothelium. LPL transported to the vascular endothelium hydrolyzes triacylglycerol (TAG) to diacylglycerol (DAG), DAG to monoacylglcerol (MAG), and MAG to glycerol with free fatty acids (FFAs) being released at each step. Parenchymal cells take up FFAs for storage or use FFAs as fuel.

• 

  Fig. 2. Novel therapeutics that modulate lipoprotein lipase activity. Apolipoproteins (APOs) and angiopoietin-like proteins (ANGPTLs) modulate lipoprotein lipase (LPL) activity: apolipoprotein C2 (APOC2) and APOC5 activate and APOC3, ANGPTL3, ANGPTL4, ANGPTL8 inhibit LPL activity. All of them are produced by the liver, while ANGPTL4 and ANGTPL8 are also produced by adipocytes. Volanesorsen and olezarsen are antisense oligonucleotides (ASOs) targeting APOC3. Evinacumab is a monoclonal antibody (Ab) inhibiting ANGPTL3. Vupanorsen is an ASO targeting ANGPTL3. Peroxisome proliferator-activated receptor alpha (PPARα) activates the transcription of LPL and stimulates LPL activity. Pemafibrate is a PPARα agonist. Omega-3 fatty acids activate both PPARα and LPL.

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