Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Apolipoprotein M is required for preβ-HDL formation and cholesterol efflux to HDL and protects against atherosclerosis


High-density lipoproteins (HDLs) are considered antiatherogenic because they mediate reverse cholesterol transport from the periphery to the liver for excretion and degradation. Here we show that mice deficient in apolipoprotein M (apoM), a component of the HDL particle, accumulated cholesterol in large HDL particles (HDL1) while the conversion of HDL to preβ-HDL was impaired. Accordingly, apoM-deficient mice lacked preβ-HDL, a subclass of lipid-poor apolipoproteins that serves as a key acceptor of peripheral cellular cholesterol. This deficiency led to a markedly reduced cholesterol efflux from macrophages to apoM-deficient HDL compared to normal HDL in vitro. Overexpression of apoM in Ldlr−/− mice protected against atherosclerosis when the mice were challenged with a cholesterol-enriched diet, showing that apoM is important for the formation of preβ-HDL and cholesterol efflux to HDL, and thereby inhibits formation of atherosclerotic lesions.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: ApoM deficiency leads to HDL1 particle formation in mice.
Figure 2: Defective HDL metabolism and lack of preβ-HDL formation in plasma of apoM-deficient mice.
Figure 3: Impaired cholesterol efflux to apoM-deficient HDL lipoproteins.
Figure 4: Adenoviral hepatic apoM overexpression protects against atherosclerosis in Ldlr−/− mice.

Accession codes




  1. Silver, D.L., Jiang, X.C., Arai, T., Bruce, C. & Tall, A.R. Receptors and lipid transfer proteins in HDL metabolism. Ann. NY Acad. Sci. 902, 103–111 (2000).

    Article  CAS  Google Scholar 

  2. Stein, O. & Stein, Y. Atheroprotective mechanisms of HDL. Atherosclerosis 144, 285–301 (1999).

    Article  CAS  Google Scholar 

  3. Assmann, G. & Nofer, J.R. Atheroprotective effects of high-density lipoproteins. Annu. Rev. Med. 54, 321–341 (2003).

    Article  CAS  Google Scholar 

  4. Fielding, C.J. & Fielding, P.E. Cellular cholesterol efflux. Biochim. Biophys. Acta 1533, 175–189 (2001).

    Article  CAS  Google Scholar 

  5. Phillips, M.C. et al. Mechanisms of high density lipoprotein-mediated efflux of cholesterol from cell plasma membranes. Atherosclerosis 137, S13–S17 (1998).

    Article  CAS  Google Scholar 

  6. Santamarina-Fojo, S., Lambert, G., Hoeg, J.M. & Brewer, H.B., Jr. Lecithin-cholesterol acyltransferase: role in lipoprotein metabolism, reverse cholesterol transport and atherosclerosis. Curr. Opin. Lipidol. 11, 267–275 (2000).

    Article  CAS  Google Scholar 

  7. Francone, O.L., Gong, E.L., Ng, D.S., Fielding, C.J. & Rubin, E.M. Expression of human lecithin-cholesterol acyltransferase in transgenic mice. Effect of human apolipoprotein AI and human apolipoprotein AII on plasma lipoprotein cholesterol metabolism. J. Clin. Invest. 96, 1440–1448 (1995).

    Article  CAS  Google Scholar 

  8. Sparks, D.L. & Pritchard, P.H. Transfer of cholesteryl ester into high density lipoprotein by cholesteryl ester transfer protein: effect of HDL lipid and apoprotein content. J. Lipid Res. 30, 1491–1498 (1989).

    CAS  PubMed  Google Scholar 

  9. Shih, D.Q. et al. Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism. Nat Genet 27, 375–382 (2001).

    Article  CAS  Google Scholar 

  10. Xu, N. & Dahlback, B. A novel human apolipoprotein (apoM). J. Biol. Chem. 274, 31286–31290 (1999).

    Article  CAS  Google Scholar 

  11. Law, S.W. et al. The molecular biology of human apoA-I, apoA-II, apoC-II and apoB. Adv. Exp. Med. Biol. 201, 151–162 (1986).

    CAS  PubMed  Google Scholar 

  12. Ashavaid, T.F., Todur, S.P. & Nair, K.G. Apolipoprotein E polymorphism and coronary heart disease. J. Assoc. Physicians India 51, 784–788 (2003).

    CAS  PubMed  Google Scholar 

  13. McFarlane, A.S. Efficient trace-labelling of proteins with iodine. Nature 182, 53 (1958).

    Article  CAS  Google Scholar 

  14. Pittman, R.C. et al. A radioiodinated, intracellularly trapped ligand for determining the sites of plasma protein degradation in vivo. Biochem. J. 212, 791–800 (1983).

    Article  CAS  Google Scholar 

  15. Rye, K.A. et al. Evidence that phospholipids play a key role in pre-beta apoA-I formation and high-density lipoprotein remodeling. Biochemistry 41, 12538–12545 (2002).

    Article  CAS  Google Scholar 

  16. Schwartz, K., Lawn, R.M. & Wade, D.P. ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR. Biochem. Biophys. Res. Commun. 274, 794–802 (2000).

    Article  CAS  Google Scholar 

  17. Puchois, P. et al. Apolipoprotein A-I containing lipoproteins in coronary artery disease. Atherosclerosis 68, 35–40 (1987).

    Article  CAS  Google Scholar 

  18. Plump, A.S., Scott, C.J. & Breslow, J.L. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse. Proc. Natl. Acad. Sci. USA 91, 9607–9611 (1994).

    Article  CAS  Google Scholar 

  19. Teupser, D., Persky, A.D. & Breslow, J.L. Induction of atherosclerosis by low-fat, semisynthetic diets in LDL receptor-deficient C57BL/6J and FVB/NJ mice: comparison of lesions of the aortic root, brachiocephalic artery, and whole aorta (en face measurement). Arterioscler. Thromb. Vasc. Biol. 23, 1907–1913 (2003).

    Article  CAS  Google Scholar 

  20. Silver, D.L., Wang, N., Xiao, X. & Tall, A.R. High density lipoprotein (HDL) particle uptake mediated by scavenger receptor class B type 1 results in selective sorting of HDL cholesterol from protein and polarized cholesterol secretion. J. Biol. Chem. 276, 25287–25293 (2001).

    Article  CAS  Google Scholar 

  21. Castro, G.R. & Fielding, C.J. Early incorporation of cell-derived cholesterol into pre-beta-migrating high-density lipoprotein. Biochemistry 27, 25–29 (1988).

    Article  CAS  Google Scholar 

  22. Barbaras, R., Puchois, P., Fruchart, J.C. & Ailhaud, G. Cholesterol efflux from cultured adipose cells is mediated by LpAI particles but not by LpAI:AII particles. Biochem. Biophys. Res. Commun. 142, 63–69 (1987).

    Article  CAS  Google Scholar 

  23. Richter, S. et al. Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1alpha: haploinsufficiency is associated with reduced serum apolipoprotein M levels. Diabetes 52, 2989–2995 (2003).

    Article  CAS  Google Scholar 

  24. Isomaa, B. et al. Chronic diabetic complications in patients with MODY3 diabetes. Diabetologia 41, 467–473 (1998).

    Article  CAS  Google Scholar 

  25. Zhang, G., Budker, V. & Wolff, J.A. High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. Hum. Gene Ther. 10, 1735–1737 (1999).

    Article  CAS  Google Scholar 

  26. O'Connor, P.M. et al. Measurement of prebeta-1 HDL in human plasma by an ultrafiltration-isotope dilution technique. Anal. Biochem. 251, 234–240 (1997).

    Article  CAS  Google Scholar 

  27. Paigen, B., Morrow, A., Holmes, P.A., Mitchell, D. & Williams, R.A. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis 68, 231–240 (1987).

    Article  CAS  Google Scholar 

Download references


This research was supported in part by an unrestricted grant from the Bristol-Myers Squibb Foundation, Inc., the Adler foundation and by a General Clinical Research Center grant (M01-RR00102) from the National Center for Research Resources at the US National Institutes of Health. We thank S. Idel and J. L. Breslow for assistance with atherosclerotic lesion quantification, for discussions and critical reading of the manuscript. We also thank T. Tuschl for advice for siRNA sequence modifications. siRNAs were kindly provided by Alnylam Pharmaceuticals, Inc.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Markus Stoffel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Immunoblot analysis of whole-liver extracts from si-luc– and si-apoM–injected C57BL/6 mice. (PDF 55 kb)

Supplementary Fig. 2

Composition of α- and preβ-HDL in human plasma. (PDF 38 kb)

Supplementary Fig. 3

Adenoviral apoM overexpression in livers of Ldlr−/− mice. (PDF 6 kb)

Supplementary Fig. 4

Increased plasma HDL levels in Ldlr−/− mice treated with Ad-apoM. (PDF 36 kb)

Supplementary Table 1

HDL-associated cholesterol levels and relative composition of isolated HDL particles in si-apoM– and Ad-apoM–treated C57BL/6 (WT) mice and in Ad-apoM–treated Tcf1−/− mice (PDF 56 kb)

Supplementary Table 2

Tissue uptake of 125I-TC-HDL2 from C57BL/6 mice (125I-TC-WT-HDL2), si-apoM–treated mice (125I-TC-si-apoM-HDL2), and Tcf1−/− mice (125I-TC-Tcf1−/−-HDL2). (PDF 35 kb)

Supplementary Table 3

Plasma concentration of cholesterol, tricglycerides, phospholipids, protein, apoM and apoAI in Ldlr−/− mice. (PDF 35 kb)

Supplementary Table 4

Plasma concentrations of cholesterol, triglycerides, phospholipids, protein, apoM and apoAI in experimental animal models. (PDF 61 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wolfrum, C., Poy, M. & Stoffel, M. Apolipoprotein M is required for preβ-HDL formation and cholesterol efflux to HDL and protects against atherosclerosis. Nat Med 11, 418–422 (2005).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing