New insights into ANGPLT3 in controlling lipoprotein metabolism and risk of cardiovascular diseases

Abstract

Dyslipidemia, characterized by elevation of plasma low density lipoprotein cholesterol (LDL-C), triglyceride (TG) and reduction of plasma high density lipoprotein cholesterol (HDL-C), has been verified as a causal risk factor for cardiovascular diseases (CVD), leading to a high mortality rate in general population. It is important to understand the molecular metabolism underlying dyslipidemia in order to reduce the risk and to develop effective therapeutic approaches against CVD. ANGPTL3 (human) or Angptl3 (mouse), one member of the angiopoietin-like protein (ANGPTL) family, has been identified as an important regulator of lipid metabolism by inhibiting LPL and EL activity. Results have demonstrated that inactivation of Angptl3 in mice could obviously reduce the level of TG, LDL-C and the atherosclerotic lesion size, leading to a lower risk for dyslipidemia and CVD. Additionally, in humans, carriers with homozygous LOF mutations in ANGPTL3 have lower plasma LDL-C, TG levels and lower risk of atherosclerosis compared to the non-carriers. Here, we collect the latest data and results, giving a new insight into the important role of ANGPTL3 in controlling lipoprotein metabolism. Finally, we introduce two update reports on the antisense oligonucleotide and monoclonal antibody-based inactivation of ANGPTL3 in human clinical trials, to identify that ANGPTL3 could be a novel and effective target for the treatment of dyslipidemia and CVD.

Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids

“…8B ). We also observed that ANGPTL3 mRNA levels were undetectable, consistent with previous reports that adipocytes do not express ANGPTL3 ( 96 ). To understand why previous researchers were unable to measure insulin stimulated ANGPTL8 release from adipocytes, we considered that ANGPTL8 might be secreted as part of an ANGPTL4/8 complex that could remain tightly bound to plasma membranes via interaction with heparin sulfate proteoglycans, thereby preventing release into the media.…”

Tissue-Specific Epigenetics of Atherosclerosis-Related ANGPT and ANGPTL Genes

“…Much of the relevance of ANGPTL8 protein to atherosclerosis involves its interaction with full-length ANGPTL3 or the biologically active C-terminal ANGPTL3 fragment, which it helps to generate [6,14,18]. ANGPTL3 , which is specifically expressed in liver, plays critical roles in determining the levels of cholesterol and triglycerides in circulating blood [15]. It has also been reported to induce endothelial cell adhesion and migration, which are correlated with angiogenesis [65].…”

“…Inhibition of LPL increases circulating levels of LDL and very LDL. Low expression of ANGPTL3 and ANGPTL8 in individuals with heterozygous inactivating mutations or in atherosclerosis mouse models correlates with a reduced risk of atherosclerosis and lower levels of lipid in the bloodstream [6,15,16]. ANGPTL3 and ANGPTL8 bind to each other and act cooperatively in their inhibition of LPL activity, which helps determine susceptibility to atherosclerosis [13,17,18].…”

Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

“…По результатам нескольких исследова-ний ANGPTL3 играет важную роль в регуляции липидного обмена, ингибируя активность липопро-теин-липазы и эндотелиальной липазы. Инактива-ция Angptl3 у мышей эффективно снижала уровень ТГ, ХС-ЛНП, а также размер атеросклеротического поражения [36], тем самым сделав ANGPTL3 новой терапевтической мишенью для лечения дислипиде-мии и ССЗ [37].…”