A Review of Progress on Targeting LDL Receptor-Dependent and -Independent Pathways for the Treatment of Hypercholesterolemia, a Major Risk Factor of ASCVD

Abstract

Since the discovery of the LDL receptor in 1973 by Brown and Goldstein as a causative protein in hypercholesterolemia, tremendous amounts of effort have gone into finding ways to manage high LDL cholesterol in familial hypercholesterolemic (HoFH and HeFH) individuals with loss-of-function mutations in the LDL receptor (LDLR) gene. Statins proved to be the first blockbuster drug, helping both HoFH and HeFH individuals by inhibiting the cholesterol synthesis pathway rate-limiting enzyme HMG-CoA reductase and inducing the LDL receptor. However, statins could not achieve the therapeutic goal of LDL. Other therapies targeting LDLR include PCSK9, which lowers LDLR by promoting LDLR degradation. Inducible degrader of LDLR (IDOL) also controls the LDLR protein, but an IDOL-based therapy is yet to be developed. Among the LDLR-independent pathways, such as angiopoietin-like 3 (ANGPTL3), apolipoprotein (apo) B, apoC-III and CETP, only ANGPTL3 offers the advantage of treating both HoFH and HeFH patients and showing relatively better preclinical and clinical efficacy in animal models and hypercholesterolemic individuals, respectively. While loss-of-LDLR-function mutations have been known for decades, gain-of-LDLR-function mutations have recently been identified in some individuals. The new information on gain of LDLR function, together with CRISPR-Cas9 genome/base editing technology to target LDLR and ANGPTL3, offers promise to HoFH and HeFH individuals who are at a higher risk of developing atherosclerotic cardiovascular disease (ASCVD).

Triglyceride-Rich Lipoprotein Metabolism: Key Regulators of Their Flux

“…As shown in Figure 7 B, in the postprandial state (when insulin levels are high), the presence of ANGPTL3 and ANGPTL8 in muscle decreases LPL activity and promotes TRL-triglyceride flow to adipose tissue. Endothelial lipase levels have also been shown to be suppressed by ANGPTL3 [ 83 , 84 , 85 ]. The key role of ANGPTL3 in this process, as well as results from animal and human loss of function studies, have uncovered the potential role of ANGPTL3 inhibitors as a therapeutic avenue for hypertriglyceridemia, as we further discuss in this review.…”

Drug development advances in human genetics‐based targets

“…Angiopoietin‐like protein 3 (ANGPTL3) is a secreted protein consisting of a signal peptide sequence, an N‐terminal helical structural domain (CCD), and a C‐terminal globular fibrinogen homologous structural domain 132–134 . ANGPTL3 is expressed predominantly in the liver and secreted into the circulatory system, 132–134 where its expression is activated by oxysterol‐stimulated hepatic X receptors 135 …”

“…The mature CCD of ANGPTL3 binds lipoprotein lipase (LPL) and endothelial lipase (EL) and efficiently inhibits their catalytic activities 133,134,147–149 . The bioactivity of LPL is a critical factor in the rate of removal of circulating TG‐rich lipoproteins (TRL) and plays a major role in TG and VLDL metabolism 133,150 .…”

“…EL is a key enzyme in the regulation of HDL‐C metabolism 151 . ANGPTL3 induces lipolysis in adipose tissue, leading to the release of FFA and glycerol from adipocytes, which results in increased hepatic VLDL synthesis 134,149 …”

Genetic Counseling and Genetic Testing for Familial Hypercholesterolemia

“…Genetic testing for FH was introduced in research many years ago, and it can now be performed in a clinical setting. In addition, several different types of LDL-lowering therapies that can adequately reduce LDL cholesterol have been developed over the past decades, including statins, ezetimibe, resins, PCSK9 inhibitors, microsomal triglyceride transfer protein (MTTP) inhibitors, and angiopoietin-like protein 3 (ANGPTL3) inhibitors [ 5 , 6 , 7 , 8 , 9 ]. Now that we have tools for the genetic diagnosis of and effective treatments for this common genetic disease, we can summarize the current status of genetic counseling and genetic testing in FH, mainly based on our experience and on the experience of other collaborators across the world.…”