title: ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors.
abstract: Hypertriglyceridemia is an independent risk factor for cardiovascular disease, and plasma triglycerides (TGs) correlate strongly with plasma apolipoprotein C-III (ApoC-III) levels. Antisense oligonucleotides (ASOs) for ApoC-III reduce plasma TGs in primates and mice, but the underlying mechanism of action remains controversial. We determined that a murine-specific ApoC-III-targeting ASO reduces fasting TG levels through a mechanism that is dependent on low-density lipoprotein receptors (LDLRs) and LDLR-related protein 1 (LRP1). ApoC-III ASO treatment lowered plasma TGs in mice lacking lipoprotein lipase (LPL), hepatic heparan sulfate proteoglycan (HSPG) receptors, LDLR, or LRP1 and in animals with combined deletion of the genes encoding HSPG receptors and LDLRs or LRP1. However, the ApoC-III ASO did not lower TG levels in mice lacking both LDLR and LRP1. LDLR and LRP1 were also required for ApoC-III ASO-induced reduction of plasma TGs in mice fed a high-fat diet, in postprandial clearance studies, and when ApoC-III-rich or ApoC-III-depleted lipoproteins were injected into mice. ASO reduction of ApoC-III had no effect on VLDL secretion, heparin-induced TG reduction, or uptake of lipids into heart and skeletal muscle. Our data indicate that ApoC-III inhibits turnover of TG-rich lipoproteins primarily through a hepatic clearance mechanism mediated by the LDLR/LRP1 axis.
authors.forename: Philip L S M
authors.initials: PL
authors.lastname: Gordts
authors.forename: Ryan
authors.initials: R
authors.lastname: Nock
authors.forename: Ni-Huiping
authors.initials: NH
authors.lastname: Son
authors.forename: Bastian
authors.initials: B
authors.lastname: Ramms
authors.forename: Irene
authors.initials: I
authors.lastname: Lew
authors.forename: Jon C
authors.initials: JC
authors.lastname: Gonzales
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Thacker
authors.forename: Debapriya
authors.initials: D
authors.lastname: Basu
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lee
authors.forename: Adam E
authors.initials: AE
authors.lastname: Mullick
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Esko
mesh_terms: D000818:Animals; D053305:Apolipoprotein C-III / Q000097:blood*; D005260:Female; D005838:Genotype; D006493:Heparin / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism; D007659:Ketones / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood*; D008099:Liver / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D053305:Apolipoprotein C-III; D007659:Ketones; D008074:Lipoproteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D014280:Triglycerides; D025521:Tumor Suppressor Proteins; C030087:lipoprotein triglyceride; D006493:Heparin