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⇱ Angptl3 regulates lipid metabolism in mice | Nature Genetics

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Abstract

The KK obese mouse is moderately obese and has abnormally high levels of plasma insulin (hyperinsulinemia), glucose (hyperglycemia) and lipids (hyperlipidemia). In one strain (KK/San), we observed abnormally low plasma lipid levels (hypolipidemia). This mutant phenotype is inherited recessively as a mendelian trait. Here we report the mapping of the hypolipidemia (hypl) locus to the middle of chromosome 4 and positional cloning of the autosomal recessive mutation responsible for the hypolipidemia. The hypl locus encodes a unique angiopoietin-like lipoprotein modulator, which we named Allm1. It is identical to angiopoietin-like protein 3, encoded by Angptl3, and has a highly conserved counterpart in humans. Overexpression of Angptl3 or intravenous injection of the purified protein in KK/San mice elicited an increase in circulating plasma lipid levels. This increase was also observed in C57BL/6J normal mice. Taken together, these data suggest that Angptl3 regulates lipid metabolism in animals.

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Figure 1: Electrophoretic analysis of plasma lipoprotein in wildtype KK, KK/San and C57BL/6J mice.
Figure 2: Plots of plasma triglyceride concentration for test-cross progeny. Individual points on the graph represent the triglyceride concentration in a mouse.
Figure 3: Genetic and physical map of the region of hypl on mouse chromosome 4.
Figure 4: Expression of Angptl3 mRNA.
Figure 5: A 4-bp nucleotide sequence insertion in exon 6 of Angptl3 in KK/San mice.
Figure 6: Plasma lipid levels after adenovirus-mediated gene transfer of Angptl3 in mice.
Figure 7: ANGPTL3 is a secreted protein.
Figure 8: Plasma lipid levels after administration of recombinant human ANGPTL3 in KK/San mice.

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Acknowledgements

This work is dedicated to the memory of N. Serizawa. We thank N. Shimizu and K. Kawasaki for help with BAC cloning; K. Maruyama for providing the pME18S vector; S. Takeshita, A. Suzuki and M. Ito for assistance with animal breeding and genetic analysis; M. Shimizu, A. Muramatsu, M. Mizuide, M. Sugawara, J. Ohsumi and S. Yoshioka for biochemical analysis; M. Nagata for anatomical analysis and K. Watanabe for protein purification. We are grateful to N. Nakamura, A. Sanbuissho and K. Yoshida for helpful discussion.

Author information

Author notes

  1. Ryuta Koishi, Yosuke Ando and Mitsuru Ono: These authors contributed equally to this work.

Authors and Affiliations

  1. Biomedical Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, 140-8710, Tokyo, Japan

    Ryuta Koishi, Mitsuru Ono, Mitsuru Shimamura, Hiroaki Yasumo & Hidehiko Furukawa

  2. Medicinal Safety Research Laboratories, Sankyo Co., Ltd., 717, Horikoshi, Fukuroi, 437-0065, Shizuoka-ken, Japan

    Yosuke Ando

  3. Pharmacology & Molecular Biology Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, 140-8710, Tokyo, Japan

    Toshihiko Fujiwara

  4. Sankyo Pharma Research Institute, 4250 Executive Square, Suite 420, La Jolla, 92037, California, USA

    Hiroyoshi Horikoshi

Authors
  1. Ryuta Koishi
  2. Yosuke Ando
  3. Mitsuru Ono
  4. Mitsuru Shimamura
  5. Hiroaki Yasumo
  6. Toshihiko Fujiwara
  7. Hiroyoshi Horikoshi
  8. Hidehiko Furukawa

Corresponding author

Correspondence to Ryuta Koishi.

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Koishi, R., Ando, Y., Ono, M. et al. Angptl3 regulates lipid metabolism in mice. Nat Genet 30, 151–157 (2002). https://doi.org/10.1038/ng814

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