TY - JOUR
T1 - Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance
AU - Adam, Rene C.
AU - Mintah, Ivory J.
AU - Alexa-Braun, Corey A.
AU - Shihanian, Lisa M.
AU - Lee, Joseph S.
AU - Banerjee, Poulabi
AU - Hamon, Sara C.
AU - Kim, Hye In
AU - Cohen, Jonathan C.
AU - Hobbs, Helen H.
AU - Van Hout, Cristopher
AU - Gromada, Jesper
AU - Murphy, Andrew J.
AU - Yancopoulos, George D.
AU - Sleeman, Mark W.
AU - Gusarova, Viktoria
N1 - Publisher Copyright:
© 2020 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.
PY - 2020/9
Y1 - 2020/9
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Cardiovascular disease
KW - Familial hypercholesterolemia
KW - Lipidomics
KW - Low density lipoprotein receptor
KW - Low density lipoprotein-cholesterol
KW - Very low density lipoprotein
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U2 - 10.1194/jlr.RA120000888
DO - 10.1194/jlr.RA120000888
M3 - Article
C2 - 32646941
AN - SCOPUS:85090252140
SN - 0022-2275
VL - 61
SP - 1271
EP - 1286
JO - Journal of lipid research
JF - Journal of lipid research
IS - 9
ER -