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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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.
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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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