Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion1[S]
Humans and mice lacking angiopoietin-like protein 3 (ANGPTL3) have pan-hypolipidemia. ANGPTL3 inhibits two intravascular lipases, LPL and endothelial lipase, and the low plasma TG and HDL-cholesterol levels in ANGPTL3 deficiency reflect increased activity of these enzymes. The mechanism responsible...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-07-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520355498 |
| _version_ | 1818690904887656448 |
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| author | Yan Wang Viktoria Gusarova Serena Banfi Jesper Gromada Jonathan C. Cohen Helen H. Hobbs |
| author_facet | Yan Wang Viktoria Gusarova Serena Banfi Jesper Gromada Jonathan C. Cohen Helen H. Hobbs |
| author_sort | Yan Wang |
| collection | DOAJ |
| description | Humans and mice lacking angiopoietin-like protein 3 (ANGPTL3) have pan-hypolipidemia. ANGPTL3 inhibits two intravascular lipases, LPL and endothelial lipase, and the low plasma TG and HDL-cholesterol levels in ANGPTL3 deficiency reflect increased activity of these enzymes. The mechanism responsible for the low LDL-cholesterol levels associated with ANGPTL3 deficiency is not known. Here we used an anti-ANGPTL3 monoclonal antibody (REGN1500) to inactivate ANGPTL3 in mice with genetic deficiencies in key proteins involved in clearance of ApoB-containing lipoproteins. REGN1500 treatment consistently reduced plasma cholesterol levels in mice in which Apoe, Ldlr, Lrp1, and Sdc1 were inactivated singly or in combination, but did not alter clearance of rabbit 125I-βVLDL or mouse 125I-LDL. Despite a 61% reduction in VLDL-TG production, VLDL-ApoB-100 production was unchanged in REGN1500-treated animals. Hepatic TG content, fatty acid synthesis, and fatty acid oxidation were similar in REGN1500 and control antibody-treated animals. Taken together, our findings indicate that inactivation of ANGPTL3 does not affect the number of ApoB-containing lipoproteins secreted by the liver but alters the particles that are made such that they are cleared more rapidly from the circulation via a noncanonical pathway(s). The increased clearance of lipolytic remnants results in decreased production of LDL in ANGPTL3-deficient animals. |
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| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-17T12:33:25Z |
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| series | Journal of Lipid Research |
| spelling | doaj.art-cfc0a060063048f0935ef330539cd2032022-12-21T21:48:27ZengElsevierJournal of Lipid Research0022-22752015-07-0156712961307Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion1[S]Yan Wang0Viktoria Gusarova1Serena Banfi2Jesper Gromada3Jonathan C. Cohen4Helen H. Hobbs5Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX; Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TXRegeneron Pharmaceuticals, Tarrytown, NYDepartments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TXRegeneron Pharmaceuticals, Tarrytown, NYTo whom correspondence should be addressed. (H.H.H.); (J.C.C.); Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX; To whom correspondence should be addressed. (H.H.H.); (J.C.C.)To whom correspondence should be addressed. (H.H.H.); (J.C.C.); Departments of Molecular Genetics University of Texas Southwestern Medical Center, Dallas, TX; Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX; To whom correspondence should be addressed. (H.H.H.); (J.C.C.)Humans and mice lacking angiopoietin-like protein 3 (ANGPTL3) have pan-hypolipidemia. ANGPTL3 inhibits two intravascular lipases, LPL and endothelial lipase, and the low plasma TG and HDL-cholesterol levels in ANGPTL3 deficiency reflect increased activity of these enzymes. The mechanism responsible for the low LDL-cholesterol levels associated with ANGPTL3 deficiency is not known. Here we used an anti-ANGPTL3 monoclonal antibody (REGN1500) to inactivate ANGPTL3 in mice with genetic deficiencies in key proteins involved in clearance of ApoB-containing lipoproteins. REGN1500 treatment consistently reduced plasma cholesterol levels in mice in which Apoe, Ldlr, Lrp1, and Sdc1 were inactivated singly or in combination, but did not alter clearance of rabbit 125I-βVLDL or mouse 125I-LDL. Despite a 61% reduction in VLDL-TG production, VLDL-ApoB-100 production was unchanged in REGN1500-treated animals. Hepatic TG content, fatty acid synthesis, and fatty acid oxidation were similar in REGN1500 and control antibody-treated animals. Taken together, our findings indicate that inactivation of ANGPTL3 does not affect the number of ApoB-containing lipoproteins secreted by the liver but alters the particles that are made such that they are cleared more rapidly from the circulation via a noncanonical pathway(s). The increased clearance of lipolytic remnants results in decreased production of LDL in ANGPTL3-deficient animals.http://www.sciencedirect.com/science/article/pii/S0022227520355498cholesteroldyslipidemiaslipase/endotheliallipase/lipoproteinangiopoietin-like protein 3very low density lipoprotein |
| spellingShingle | Yan Wang Viktoria Gusarova Serena Banfi Jesper Gromada Jonathan C. Cohen Helen H. Hobbs Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion1[S] Journal of Lipid Research cholesterol dyslipidemias lipase/endothelial lipase/lipoprotein angiopoietin-like protein 3 very low density lipoprotein |
| title | Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion1[S] |
| title_full | Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion1[S] |
| title_fullStr | Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion1[S] |
| title_full_unstemmed | Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion1[S] |
| title_short | Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion1[S] |
| title_sort | inactivation of angptl3 reduces hepatic vldl triglyceride secretion1 s |
| topic | cholesterol dyslipidemias lipase/endothelial lipase/lipoprotein angiopoietin-like protein 3 very low density lipoprotein |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520355498 |
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