title: A lipasin/Angptl8 monoclonal antibody lowers mouse serum triglycerides involving increased postprandial activity of the cardiac lipoprotein lipase.
abstract: Lipasin/Angptl8 is a feeding-induced hepatokine that regulates triglyceride (TAG) metabolism; its therapeutical potential, mechanism of action, and relation to the lipoprotein lipase (LPL), however, remain elusive. We generated five monoclonal lipasin antibodies, among which one lowered the serum TAG level when injected into mice, and the epitope was determined to be EIQVEE. Lipasin-deficient mice exhibited elevated postprandial activity of LPL in the heart and skeletal muscle, but not in white adipose tissue (WAT), suggesting that lipasin suppresses the activity of LPL specifically in cardiac and skeletal muscles. Consistently, mice injected with the effective antibody or with lipasin deficiency had increased postprandial cardiac LPL activity and lower TAG levels only in the fed state. These results suggest that lipasin acts, at least in part, in an endocrine manner. We propose the following model: feeding induces lipasin, activating the lipasin-Angptl3 pathway, which inhibits LPL in cardiac and skeletal muscles to direct circulating TAG to WAT for storage; conversely, fasting induces Angptl4, which inhibits LPL in WAT to direct circulating TAG to cardiac and skeletal muscles for oxidation. This model suggests a general mechanism by which TAG trafficking is coordinated by lipasin, Angptl3 and Angptl4 at different nutritional statuses.
authors.affiliation: Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, 540 East Canfield Street, Detroit, MI 48201, USA.
authors.forename: Zhiyao
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Division of Endocrinology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.|Department of Medicine, Hamad Medical Corporation, Doha, Qatar.
authors.forename: Abdul B
authors.initials: AB
authors.lastname: Abou-Samra
authors.affiliation: Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, 540 East Canfield Street, Detroit, MI 48201, USA.|Division of Endocrinology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Ren
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000091303:Angiopoietin-Like Protein 3; D000075803:Angiopoietin-Like Protein 4; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D006801:Humans; D008071:Lipoprotein Lipase / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D036361:Peptide Hormones / Q000172:deficiency / Q000276:immunology* / Q000627:therapeutic use; D019518:Postprandial Period; D014280:Triglycerides / Q000097:blood
chemical_list: C000595899:ANGPTL8 protein, mouse; D000091303:Angiopoietin-Like Protein 3; D000075803:Angiopoietin-Like Protein 4; D000091306:Angiopoietin-Like Protein 8; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C404495:Angptl3 protein, mouse; C407088:Angptl4 protein, mouse; D000911:Antibodies, Monoclonal; D036361:Peptide Hormones; D014280:Triglycerides; D008071:Lipoprotein Lipase