The Potential of ANGPTL8 Antagonism to Simultaneously Reduce Triglyceride and Increase HDL-Cholesterol Plasma Levels.

Ren Zhang

doi:10.3389/fcvm.2021.795370

Abstract

Elevated triglyceride (TG) and reduced high-density lipoprotein-cholesterol (HDL-C) plasma levels are risk factors for atherosclerosis and cardiovascular disease. Therefore, a drug that simultaneously reduces TG and increases HDL-C plasma levels has the potential to prevent and treat these diseases. Angiopoietin-like 3 (ANGPTL3) regulates plasma TG and HDL-C levels by inhibiting lipoprotein lipase (LPL) and endothelial lipase (EL), respectively. ANGPTL3 inhibition of LPL requires complex formation with ANGPTL8, which is not required for its inhibition of EL. Therefore, the entire pool of plasma ANGPTL3 can be classified as ANGPTL8-associated ANGPTL3 and ANGPTL8-free ANGPTL3, where the former inhibits LPL and the latter inhibits EL. ANGPTL8 antibodies or inhibitors that block its interactions with ANGPTL3 can disrupt or preclude the ANGPTL3-8 complex formation, resulting in fewer ANGPTL3-8 complexes (reduced LPL inhibition), but more free ANGPTL3 (enhanced EL inhibition). Therefore, ANGPTL8 antagonism increases LPL activity while decreasing EL activity, thus leading to reduced plasma TG while simultaneously increasing HDL-C levels. In humans, carriers of ANGPTL8 truncating variants consistently have lower TG but higher HDL-C levels, supporting this hypothesis.

Highlights

Elevated triglyceride (TG) and reduced high-density lipoprotein-cholesterol (HDL-C) plasma levels are risk factors for atherosclerosis and cardiovascular disease [1]
This study, which is based on an independent SNP and an independent population, shows consistent results, and supports the hypothesis that Angiopoietin-like 8 (ANGPTL8) inhibition results in lower TG but higher HDL-C levels [13] (Table 1)
The hypothesis holds true, whether or not ANGPTL8 increases Angiopoietin-like 3 (ANGPTL3)’s endothelial lipase (EL)-inhibiting activity [9, 15], because when ANGPTL3-8 complexes are disrupted, fewer ANGPTL3-8 complexes and more free ANGPTL3 still lead to higher lipoprotein lipase (LPL) and lower EL activities, respectively

Summary

INTRODUCTION

Elevated triglyceride (TG) and reduced high-density lipoprotein-cholesterol (HDL-C) plasma levels are risk factors for atherosclerosis and cardiovascular disease [1]. We would expect that more circulating ANGPTL3-8 complexes cause (a) enhanced LPL inhibition, elevated plasma TG, and (b) less free ANGPTL3, reduced EL inhibition and lower plasma HDL-C. This study, which is based on an independent SNP and an independent population, shows consistent results, and supports the hypothesis that ANGPTL8 inhibition results in lower TG but higher HDL-C levels [13] (Table 1). According to the FinnGen study, in carriers of the T allele of the ANGPTL8 SNP (rs760351239), the odds of coronary artery disease were 47% lower than in non-carriers [13] This result supports the possibility that lowered TG and elevated HDL-C levels by ANGPTL8 inhibition could translate into reduced cardiovascular disease risks. The hypothesis holds true, whether or not ANGPTL8 increases ANGPTL3’s EL-inhibiting activity [9, 15], because when ANGPTL3-8 complexes are disrupted, fewer ANGPTL3-8 complexes and more free ANGPTL3 still lead to higher LPL and lower EL activities, respectively

CONCLUSION

Findings

DATA AVAILABILITY STATEMENT