Lipids and Lipoproteins: Metabolism, Regulation, and Signaling
The Signal Peptide Anchors Apolipoprotein M in Plasma Lipoproteins and Prevents Rapid Clearance of Apolipoprotein M from Plasma*

https://doi.org/10.1074/jbc.M800695200Get rights and content
Under a Creative Commons license
open access

Lipoproteins consist of lipids solubilized by apolipoproteins. The lipid-binding structural motifs of apolipoproteins include amphipathic α-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 apoMQ22A cDNA in the liver (apoMQ22A-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 apoMQ22A 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 apoMQ22A-Tg mice. Nevertheless, human apoM was not detectable in plasma of apoMQ22A-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 apoMQ22A-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.

Cited by (0)

*

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.