title: ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase.
abstract: KK/San is a mutant mouse strain established in our laboratory from KK obese mice. KK/San mice show low plasma lipid levels compared with wild-type KK mice despite showing signs of hyperglycemia and hyperinsulinemia. Recently, we identified a mutation in the gene encoding angiopoietin-like protein 3 (Angptl3) in KK/San mice, and injection of adenoviruses encoding Angptl3 or recombinant ANGPTL3 protein to mutant KK/San mice raised plasma lipid levels. To elucidate the regulatory mechanism of ANGPTL3 on lipid metabolism, we focused on the metabolic pathways of triglyceride in the present study. Overexpression of Angptl3 in KK/San mice resulted in a marked increase of triglyceride-enriched very low density lipoprotein (VLDL). In vivo studies using Triton WR1339 revealed that there is no significant difference between mutant and wild-type KK mice in the hepatic VLDL triglyceride secretion rate. However, turnover studies using radiolabeled VLDL revealed that the clearance of (3)H-triglyceride-labeled VLDL was significantly enhanced in KK/San mice, whereas the clearance of (125)I-labeled VLDL was only slightly enhanced. In vitro analysis of recombinant protein revealed that ANGPTL3 directly inhibits LPL activity. These data strongly support the hypothesis that ANGPTL3 is a new class of lipid metabolism modulator, which regulates VLDL triglyceride levels through the inhibition of LPL activity.
authors.affiliation: Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd., 2-58 Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. tsimiz@shina.sankyo.co.jp
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shimizugawa
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ono
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shimamura
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ando
authors.forename: Ryuta
authors.initials: R
authors.lastname: Koishi
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Ueda
authors.forename: Toshimori
authors.initials: T
authors.lastname: Inaba
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Minekura
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kohama
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Furukawa
mesh_terms: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008049:Lipase / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C404495:Angptl3 protein, mouse; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008055:Lipids; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D008049:Lipase; D008071:Lipoprotein Lipase