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J. Biol. Chem., Vol. 283, Issue 27, 18765-18772, July 4, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/27/18765    most recent M800695200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Christoffersen, C. Articles by Nielsen, L. B. Search for Related Content PubMed PubMed Citation Articles by Christoffersen, C. Articles by Nielsen, L. B. Social Bookmarking                      What's this?

The Signal Peptide Anchors Apolipoprotein M in Plasma Lipoproteins and Prevents Rapid Clearance of Apolipoprotein M from Plasma^*

Christina Christoffersen¹, Josefin Ahnström, Olof Axler, Erik Ilsø Christensen^¶, Björn Dahlbäck, and Lars Bo Nielsen^||2

From the Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark, the Department of Laboratory Medicine, Division of Clinical Chemistry, University of Lund, University Hospital, S-214 01 Malmö, Sweden, the ^¶Department of Cell Biology, Institute of Anatomy, University of Aarhus, 8000 Aarhus, Denmark, and the ^||Department of Biomedical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark

Lipoproteins consist of lipids solubilized by apolipoproteins. The lipid-binding structural motifs of apolipoproteins include amphipathic -helixes and β-sheets. Plasma apolipoprotein (apo) M lacks an external amphipathic motif but, nevertheless, is exclusively associated with lipoproteins (mainly high density lipoprotein). Uniquely, however, apoM is secreted to plasma without cleavage of its hydrophobic NH₂-terminal signal peptide. To test whether the signal peptide serves as a lipoprotein anchor for apoM in plasma, we generated mice expressing a mutated apoM^Q22A cDNA in the liver (apoM^Q22A-Tg mice (transgenic mice)) and compared them with mice expressing wild-type human apoM (apoM-Tg mice). The substitution of the amino acid glutamine 22 with alanine in apoM^Q22A results in secretion of human apoM without a signal peptide. The human apoM mRNA level in liver and the amount of human apoM protein secretion from hepatocytes were similar in apoM-Tg and apoM^Q22A-Tg mice. Nevertheless, human apoM was not detectable in plasma of apoM^Q22A-Tg mice, whereas it was easily measured in the apoM-Tg mice. To examine the plasma metabolism, recombinant apoM lacking the signal peptide was produced in Escherichia coli and injected into wild-type mice. The apoM without signal peptide did not associate with lipoproteins and was rapidly cleared in the kidney. Accordingly, ligation of the kidney arteries in apoM^Q22A-Tg mice resulted in rapid accumulation of human apoM in plasma. The data suggest that hydrophobic signal peptide sequences, if preserved upon secretion, can anchor plasma proteins in lipoproteins. In the case of apoM, this mechanism prevents rapid loss by filtration in the kidney.

Received for publication, January 28, 2008 , and in revised form, April 10, 2008.

^* This work was supported by The Danish Heart Foundation Grants 02-1-2-24-22980 (to L. B. N.) and 06-4-B522-A918-22286 (to C. C.) and by grants from the Rigshospitalet, University of Copenhagen (to L. B. N.), the Gerda and Aage Haensch's Foundation, Denmark (to C. C.), The Swedish Science Council (Grant 07143 to B. D.), The Swedish Heart-Lung Foundation (to B. D.), and Påhlsson's Foundation (to B. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Dept. of Clinical Biochemistry, KB3011, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: 45-3545-3011; Fax: 45-3545-2524; E-mail: christina.christoffersen{at}rh.regionh.dk. ² To whom correspondence may be addressed: Dept. of Clinical Biochemistry, KB3011, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: 45-3545-3011; Fax: 45-3545-2524; E-mail: larsbo{at}rh.dk.

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