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

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.

Sanghuangporus vaninii extract ameliorates hyperlipidemia in rats by mechanisms identified with transcriptome analysis

“…In lipid metabolism, lipoprotein lipase (LPL) hydrolyzes triglycerides packed in circulating chylomicrons and very low‐density lipoprotein (VLDL) into free fatty acids, so that consequently the triglycerides are cleared from bloodstream and in this way the lipid levels are regulated (Wu et al., 2021 ). Mutations in the LPL gene can lead to type I hyperlipoproteinemia (Pingitore et al., 2016 ) and LPL is also considered to be a key target for many lipid‐lowering agents (Moon et al., 2022 ). Similarly, angiopoietin like protein 8 (ANGPTL8), the latest member of the ANGPTL family, is also regarded as a potential target for anti‐hyperlipidemia due to its ability to inhibit LPL activity by interacting with ANGPTL3, and then regulate plasma TG levels (Li et al., 2021 ; Sylvers‐Davie & Davies, 2021 ).…”

Targeting host-specific metabolic pathways—opportunities and challenges for anti-infective therapy

“…Potential targets for novel lipid lowering therapeutics have been identified, including the LDL receptor, PCSK9, the angiopoietin-like (ANGPTL) family, apolipoproteins (APOs) and LPL. These proteins have been the focus to develop novel therapeutics to treat hypertriacylglycerolemia in patients who do not reach the target goal of TG after using the currently available drugs, based on genetic studies of altered lipid phenotypes in the proteins regulating LPL activity, ( Moon et al, 2022 ). A monoclonal antibody, Evinacumab, inhibiting ANGPTL3, is approved for use in the United States in patients with homozygous familial hypercholesterolemia.…”

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“…TG packed in VLDL or CM is hydrolyzed to free fatty acid by lipoprotein lipase (LPL) ( Fig. 3 ) [ 41 ]. The expression of LPL is downregulated under uremic condition [ 42 ].…”