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ANGPTL3 Decreases Very Low Density Lipoprotein Triglyceride Clearance by Inhibition of Lipoprotein Lipase

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...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-09, Vol.277 (37), p.33742-33748
Main Authors: Shimizugawa, Tetsuya, Ono, Mitsuru, Shimamura, Mitsuru, Yoshida, Kenichi, Ando, Yosuke, Koishi, Ryuta, Ueda, Kenjiro, Inaba, Toshimori, Minekura, Hiroyuki, Kohama, Takafumi, Furukawa, Hidehiko
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Language:English
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Summary: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 encodingAngptl3 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 ofAngptl3 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 of3H-triglyceride-labeled VLDL was significantly enhanced in KK/San mice, whereas the clearance of 125I-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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M203215200