Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance

Journal of Lipid Research

Cristopher Van Hout¹  Helen H. Hobbs²  Jonathan C. Cohen³  Jesper Gromada⁴  Hye In Kim⁴  Mark W. Sleeman⁵  Lisa M. Shihanian⁵  Viktoria Gusarova⁵  Ivory J. Mintah⁵  Andrew J. Murphy⁵  Corey A. Alexa-Braun⁵  Sara C. Hamon⁵  Poulabi Banerjee⁵  George D. Yancopoulos⁵  Rene C. Adam⁵  Joseph S. Lee⁵ 

[1] Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA;Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA;Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA;Regeneron Genetics Center, Tarrytown, NY, USA;Regeneron Pharmaceuticals, Tarrytown, NY, USA;

关键词: atherosclerosis;    cardiovascular disease;    familial hypercholesterolemia;    low density lipoprotein-cholesterol;    low density lipoprotein receptor;    lipidomics;   

DOI  :  

来源: DOAJ

【 摘 要 】

Angiopoietin-like protein (ANGPTL)3 regulates plasma lipids by inhibiting LPL and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-C independently of the classical LDLR-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic, and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3's novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.

【 授权许可】

Unknown