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

Nature Medicine volume 11, pages 418–422 (2005)Cite this article

Abstract

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.

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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.

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Acknowledgements

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.

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  1. The Laboratory of Metabolic Diseases, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA

    Christian Wolfrum, Matthew N Poy & Markus Stoffel

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  1. Christian Wolfrum
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  2. Matthew N Poy
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  3. Markus Stoffel
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Correspondence to Markus Stoffel.

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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)

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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). https://doi.org/10.1038/nm1211

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