Angptl3 regulates lipid metabolism in mice


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.

Accession codes




  1. 1

    Stanbury, J.B., Wyngaarden, J.B., Goldstein, J.L. & Brown, M.S. in The Metabolic Basis of Inherited Disease 5th edn (eds Herbert, P.N., Assmann, G., Gotto, A.M. Jr & Fredrickson, D.S.) 589–621 (McGraw-Hill, New York, 1983).

    Google Scholar 

  2. 2

    Wetterau, J.R. et al. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science 258, 999–1001 (1992).

    CAS  Article  Google Scholar 

  3. 3

    Shoulders, C.C. et al. Abetalipoproteinemia is caused by defects of the gene encoding the 97 kDa subunit of a microsomal triglyceride transfer protein. Hum. Mol. Genet. 2, 2109–2116 (1993).

    CAS  Article  Google Scholar 

  4. 4

    Sharp, D. et al. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinemia. Nature 365, 65–69 (1993).

    CAS  Article  Google Scholar 

  5. 5

    Rehberg, E.F. et al. A novel abetalipoproteinemia genotype. Identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase. J. Biol. Chem. 271, 29945–29952 (1996).

    CAS  Article  Google Scholar 

  6. 6

    Narcisi, T.M. et al. Mutations of the microsomal triglyceride transfer-protein gene in abetalipoproteinemia. Am. J. Hum. Genet. 57, 1298–1310 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Farese, R.V., Linton, M.F. & Young, S.G. Apolipoprotein-B gene mutations affecting cholesterol levels. J. Int. Med. 231, 643–652 (1992).

    CAS  Article  Google Scholar 

  8. 8

    Schonfeld, G. The hypobetalipoproteinemias. Annu. Rev. Nutr. 15, 23–34 (1995).

    CAS  Article  Google Scholar 

  9. 9

    Talmud, P.J. et al. Donor splice mutation generates a lipid-associated apolipoprotein B-27.6 in a patient with homozygous hypobetalipoproteinemia. J. Lipid Res. 35, 468–477 (1994).

    CAS  PubMed  Google Scholar 

  10. 10

    Welty, F.K., Ordovas, J., Schaefer, E.J., Wilson, P.W.F. & Young, S.G. Identification and molecular analysis of two apoB gene mutations causing low plasma cholesterol levels. Circulation 92, 2036–2040 (1995).

    CAS  Article  Google Scholar 

  11. 11

    Parhofer, K.G., Barrett, P.H.R., Bier, D.M. & Schonfeld, G. Positive linear correlations between the length of truncated apolipoprotein B and its secretion rate: in vivo studies in apoB-89, apoB-75, apoB-54.8, and apoB-31 heterozygotes. J. Lipid Res. 37, 844–852 (1996).

    CAS  PubMed  Google Scholar 

  12. 12

    Brooks-Wilson, A. et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nature Genet. 22, 336–345 (1999).

    CAS  Article  Google Scholar 

  13. 13

    Bodzioch, M. et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nature Genet. 22, 347–351 (1999).

    CAS  Article  Google Scholar 

  14. 14

    Rust, S. et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nature Genet. 22, 352–355 (1999).

    CAS  Article  Google Scholar 

  15. 15

    Reue, K. & Doolittle, M.H. Naturally occurring mutations in mice affecting lipid transport and metabolism. J. Lipid Res. 37, 1387–1405 (1996).

    CAS  PubMed  Google Scholar 

  16. 16

    Welsh, C.L. et al. Genetic regulation of cholesterol homeostasis: chromosomal organization of candidate genes. J. Lipid Res. 37, 1406–1421 (1996).

    Google Scholar 

  17. 17

    Purcell-Huynh, D.A. et al. Genetic factors in lipoprotein metabolism. Analysis of a genetic cross between inbred mouse strains NZB/BINJ and SM/J using a complete linkage map approach. J. Clin. Invest. 96, 1845–1858 (1995).

    CAS  Article  Google Scholar 

  18. 18

    Kondo, K., Nozawa, K., Tomita, T. & Ezaki, K. Inbred strains resulting from Japanese mice. Bulletin of the Experimental Animals 6, 107–112 (1957).

    Article  Google Scholar 

  19. 19

    Nakamura, M. & Yamada, K. Studies on a diabetic (KK) strain of mice. Diabetologia 3, 212–221 (1967).

    CAS  Article  Google Scholar 

  20. 20

    Nakamura, M. A diabetic strain of the mouse. Proc. Jpn. Acad. 38, 348–352 (1962).

    Article  Google Scholar 

  21. 21

    Conklin, D. et al. Identification of mammalian angiopoietin-related protein expressed specifically in liver. Genomics 62, 477–482 (1999).

    CAS  Article  Google Scholar 

  22. 22

    Shiraki, T., Yoshioka, S. & Horikoshi, H. Difference of triglyceride metabolism between two colonies of diabetic KK-mice. Diabetes Frontier 4, 641 (1993).

    Google Scholar 

  23. 23

    Fujiwara, T. et al. Identification and chromosomal assignment of USP1, a novel gene encoding a human ubiquitin-specific protease. Genomics 54, 155–158 (1998).

    CAS  Article  Google Scholar 

  24. 24

    Reaven, G.M. Non-insulin-dependent diabetes mellitus, abnormal lipoprotein metabolism, and atherosclerosis. Metabolism 36, 1–8 (1987).

    CAS  Article  Google Scholar 

  25. 25

    Greenfield, M., Kolterman, O., Olesfsky, J. & Reaven, G.M. Mechanism of hypertriglyceridaemia in diabetic patients with fasting hyperglycaemia. Diabetologia 18, 441–446 (1980).

    CAS  Article  Google Scholar 

  26. 26

    Greenfield, M.S., Doberne, L., Rosenthal, M., Vreman, H.J. & Reaven, G.M. Lipid metabolism in non-insulin-dependent diabetes mellitus: effect of glipizide therapy. Arch. Intern. Med. 142, 1498–1500 (1982).

    CAS  Article  Google Scholar 

  27. 27

    Davis, S. et al. Isolation of angiopoietin-1, a ligand for the Tie2 receptor, by secretion-trap expression cloning. Cell 87, 1161–1169 (1996).

    CAS  Article  Google Scholar 

  28. 28

    Maisonpierre, P.C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55–60 (1997).

    CAS  Article  Google Scholar 

  29. 29

    Valenzuela, D.M. et al. Angiopoietin 3 and 4: diverging gene counterparts in mice and humans. Proc. Natl Acad. Sci. USA 96, 1904–1909 (1999).

    CAS  Article  Google Scholar 

  30. 30

    Procopio, W.N., Pelavin, P.I., Lee, W.M.F. & Yeilding, N.M. Angiopoietin-1 and –2 coiled coil domains mediate distinct homo-oligomerization patterns, but fibrinogen-like domains mediate ligand activity. J. Biol. Chem. 274, 30196–30201 (1999).

    CAS  Article  Google Scholar 

  31. 31

    Brunzell, J.D., Schrott, H.G., Motulsky, A.G. & Bierman, E.L. Myocardial infarction in the familial forms of hypertriglyceridemia. Metabolism 25, 313–320 (1976).

    CAS  Article  Google Scholar 

  32. 32

    Goldstein, J.L., Schrott, H.G., Hazzard, W.R., Bierman, E.L. & Motulsky, A.G. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J.Clin. Invest. 52, 1544–1568 (1973).

    CAS  Article  Google Scholar 

  33. 33

    Genest, J.J. Jr et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation 85, 2025–2033 (1992).

    Article  Google Scholar 

  34. 34

    Schaefer, E.J., Genest, J.J. Jr, Ordovas, J.M., Salem, D.N. & Wilson, P.W. Familial lipoprotein disorders and premature coronary artery disease. Atherosclerosis 108, S41–S54 (1994).

    Article  Google Scholar 

  35. 35

    Lander, E.S. et al. MAPMAKER: an interactive computer package for constructing primary genetic linkage maps of experimental and natural populations. Genomics 1, 174–181 (1987).

    CAS  Article  Google Scholar 

  36. 36

    Miyake, S. et al. Efficient generation of recombinant adenoviruses using adenovirus DNA-terminal protein complex and a cosmid bearing the full-length virus genome. Proc. Natl Acad. Sci. USA 93, 1320–1324 (1996).

    CAS  Article  Google Scholar 

  37. 37

    Kanegae, Y., Makimura, M. & Saito, I. A simple and efficient method for purification of infectious recombinant adenovirus. Jpn. J. Med. Sci. Biol. 47, 157–166 (1994).

    CAS  Article  Google Scholar 

  38. 38

    Laemmli, U.K. Cleavage of structure proteins during the assembly of the head of bacteriophage T4. Nature 227, 680–685 (1970).

    CAS  Article  Google Scholar 

Download references


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



Corresponding author

Correspondence to Ryuta Koishi.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Koishi, R., Ando, Y., Ono, M. et al. Angptl3 regulates lipid metabolism in mice. Nat Genet 30, 151–157 (2002).

Download citation

Further reading


Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing